Limbic Anatomy and Physiology

Chapter 30

Dan C. McIntyre

Philip A. Schwartzkroin

Introduction

The concept of a “limbic lobe” was first put forth by Broca²⁷ as a means of labeling the various structures that surround the brainstem and form the border of the ventricular system. Broca was responsible also for the view of these structures as primarily olfactory in function (a major input from olfactory lobes)—i.e., as a “smell brain” (rhinencephalon). Based on anatomic grounds, Papez¹⁸² proposed the existence of a network of limbic structures—including the hypothalamus, anterior thalamus, cingulate cortex, and hippocampus—that was responsible for emotional behavior. The amygdala was not included in the initial description of the Papez circuit, but Maclean¹³⁹ subsequently expanded Papez’s view of the anatomy of emotion to include the amygdala and several parahippocampal structures; he called this expanded network the limbic system. Although both Papez and Maclean viewed the hippocampus as central to the limbic system concept of emotion, we now know that emotional behavior is more strongly supported by the amygdala.¹⁵¹^,²⁰¹^,²⁷¹ In contrast, the central position of the hippocampus in the limbic system has more recently focused on its role in memory⁶¹^,²²⁸^,²²⁹^,²⁴⁷ and its contributions to temporal lobe epilepsy (TLE).⁷⁴

Of the various epileptic disorders seen in humans, the most frequently observed are those of temporal-lobe origin.⁶² Considering the pathogenesis of the temporal lobe seizures, one often (but not always) finds a sclerotic lesion in one or more of the limbic or mesial temporal structures (see Chapter 13). These mesial structures form part of an olfactory–neocortical network that involves the hippocampus; the entorhinal, perirhinal, and piriform cortices; and the amygdala. The cells contained within these structures have both intrinsic properties and local connections that, when sufficiently provoked, can provide strong recurrent excitation that leads to robust seizure activity. The strong communication between these structures can amplify the seizure event and recruit cells with efferent connections that distribute widely throughout the brain. It is of little surprise, therefore, that discrete electrical stimulation in several of these same mesial structures can reproduce, in an epileptic patient, many of the features of the patient’s automatism,²⁵⁹ and that surgical resection of the structures can provide relief from the seizures.⁶³ With this evidence in mind, we briefly review both anatomic and physiologic features of the hippocampus, entorhinal cortex, perirhinal and piriform cortices, and amygdala. A description of the normal structure and function of these “limbic”/mesial temporal structures is critical for our understanding of their roles in the development, study,¹²⁶ and expression of TLE.⁷³

The Hippocampal Formation

The hippocampal formation has attracted considerable attention during the recent explosion of interest in cellular and synaptic neuroscience.²¹⁵^,²¹⁸ Its attraction as a focus for research stems from several considerations: (a) It is a region of the brain implicated in a number of important (and interesting) “normal” behaviors, such as learning and memory; (b) both functionally and structurally, the hippocampus shows an unusual degree of neuronal “plasticity”¹²⁹^,¹⁷²^,²¹⁴; (c) it has been implicated as a focus of pathology in a number of neurologic disorders ranging from epilepsy to global ischemia,²⁴ Alzheimer disease,¹⁶¹ traumatic head injury,²⁶¹ to psychiatric disorders³⁸; (d) its unique, laminated structure has made it particularly conducive to study using in vitro brain slice preparations, an approach that has been adopted by many laboratories; (e) it can be viewed as a somewhat simplified cortex; and (f) it is richly connected to other parts of the limbic system (Fig. 1). The archicortical hippocampal circuitry has served as a “model” for the more complex neocortex, and the hippocampal pyramidal cell has been studied and characterized as a model central nervous system (CNS) neuron. Given the interest and activity of so many investigators, a large store of information is available about hippocampal cell properties, structure, afferents and efferents, receptors and transmitters, and local circuits. This chapter deals primarily with major points of organization and function that have potential implications for our understanding of epilepsy-related phenomena.

Regional Connectivity

The hippocampal formation is conventionally divided into four major cell regions: Subiculum, cornu ammonis regio superior (CA1), cornu ammonis regio inferior (CA3), and the dentate gyrus (Fig. 1). Each region is defined, at least in part, by its unique patterns of input and output, as well as by the features of its principal cell population. Part of the beauty and simplicity of the hippocampus is in the early established finding that each region projects to the next through an excitatory “trisynaptic” pathway⁷ (see Fig. 1). Thus, the granule cells of the dentate gyrus send their mossy fiber axons to the CA3 region (the CA2 transition zone, by definition, receives no mossy fiber input); axon branches of the CA3 pyramidal cells—the Schaffer collaterals—project to CA1; the CA1 pyramidal cells send axons to the subiculum; and the subiculum projects out of the hippocampal formation (back to entorhinal cortex as well as other cortical targets). Recent studies have suggested that this simple view of an intrahippocampal organization is unrealistic⁷ and perhaps even misleading in our efforts to learn how information is processed through the hippocampus. We now know, for example, (a) that the mossy fibers also make numerous contacts within the dentate hilus and that they colocalize opioid peptides¹⁵² and zinc,⁶⁸ along with glutamate; (b) that the CA3 cells project to contralateral hippocampus, as well as back into the ipsilateral dentate hilus, where they excite mossy cells and interneurons⁶⁵^,¹²⁷; (c) that activity in the CA1 pyramidal region can influence activity in the CA3

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pyramidal cells, perhaps through antidromic mechanisms²³³; (d) and that hilar neurons interconnect ipsilateral and contralateral dentate regions.²⁰⁰ Further, although it appears that each of the major associational connections uses the excitatory neurotransmitter, glutamate, the nature of the evoked post-synaptic potentials in each region may be rather different. For example, the mossy fiber unitary excitatory postsynaptic potential (EPSP) onto CA3 pyramidal cells is very large (millivolts) and mediated primarily by non-N-methyl-D-aspartate (NMDA) glutamate receptors²⁷⁰; in contrast, the unitary EPSP produced by Schaffer collateral synapses onto CA1 pyramidal cells is more typical in size (about 100 μV) and involves both non-NMDA and NMDA receptor components.²⁰⁴ Finally, hippocampal “interneurons” contribute a γ-aminobutyric acid (GABA)ergic component to interregional, as well as local intraregional, information relay.²¹⁹ Thus, what was once thought to be a simple, serial, feed-forward intrahippocampal pathway is now known to be an elaborate series of interacting and parallel feed-forward and feedback circuits, involving not only principal cell axons but also specialized interneuronal interactions (Fig. 2).

FIGURE 1. Major connections of the limbic system. Diagram of the major interconnections among principal limbic system structures, in particular, those regions described in the current review. EC, hippocampal formation, entorhinal cortex; PERI, perirhinal cortex; PIR, piriform cortex; AMYG, amygdala. Their connections are shown with: NEO CTX, neocortex (with no specification of cortical region); SEP, septum; HYPOTHAL, hypothalamus; THAL, thalamus; and brainstem structures LC, locus ceruleus; raphe; and SN/VTA, substantia nigra/ventral tegmental area.

FIGURE 2. Feed-forward and feedback circuits. The limbic system (and its components) is entwined in a large number of feedback control circuits from interregional to local cellular levels. A: Hippocampal modulation of the hypothalamic-pituitary-adrenal (HPA) axis via adrenal steroid influences on hippocampal neurons. Hippocampal projections to hypothalamus help to regulate release of corticotropin-releasing hormone (CRH); hypothalamic release of CRH controls pituitary output of adrenocorticotropic hormone (ACTH); ACTH acts on the adrenal glands to stimulate secretion of cortisol. Because hippocampus has a high density of adrenal steroid receptors, the level of circulating cortisol modulates hippocampal output. B: Feed-forward and feedback circuits among limbic system regions. The well-studied feed-forward circuit from entorhinal cortex to dentate gyrus (DG), from DG to hippocampus proper and from hippocampus to septum is regulated by a number of feedback steps, including: (a) hippocampal projections “back” to the dentate gyrus; (b) septal projections to the hippocampus, dentate gyrus, and entorhinal cortex; and (c) hippocampal projections to the entorhinal cortex. C: Feedback circuits that modulate “serial” processing within the hippocampus. Granule cell output to the hilus and CA3 is modulated by CA3 feedback to hilar neurons (and perhaps directly to the granule cells) and by hilar feedback from mossy cells and interneurons to the granule cells. D: Local feedback control within a given area of hippocampus. The principal cell (P) (e.g., the granule cell or the pyramidal cell) receives excitatory afferent input and sends an excitatory output, not only to the next principal cell region, but also to local inhibitory cells (Int). Local interneurons provide inhibitory feedback onto the principal cell and onto other inhibitory interneurons in the region.

FIGURE 3. Laminar organization of hippocampal subregions. Schematic diagrams on local inhibitory interneurons and various afferent inputs (with associated transmitter type) in the CA3 region (A), the CA1 region (B), and the dentate/granule cell region (C). A: In CA3, the temporal ammonic (TA), commissural (COM), associational (ASSOC), and mossy fiber (MF) afferents all make excitatory glutamatergic (Glu) synapses on pyramidal cell dendrites (both apical and basal). Other inputs (e.g., from the septum and locus ceruleus) use other neurotransmitters (acetylcholine [Ach] and norepinephrine [NE]). Locally, inhibitory interneurons (stratum radiatum [SR] cells, basal dendritic [BD] cells, basket cells [BC], and axo-axonic [AA] cells) elaborate axons targeted to particular layers. B: A similar organization can be seen in CA1 with respect to both afferent inputs and to local inhibitory cell types (oriens alveus [A], oriens [O], basket cells [BC], axo-axonic [AA], and lacunosum-moleculare [L-M]); as seen in the CA3, these interneurons send axon terminals to different layers of CA1, where they make inhibitory (GABAergic) synaptic contacts. C: In the dentate, the perforant path (PP) input from entorhinal cortex contributes excitatory glutamatergic drive onto the granule cells. The local inhibitory cell types in the dentate include axo-axonics (AA), basket cells (BC), hilar cells of different types (HICAP, hilar cell with axon in the commissural/associational pathway; HIPP, hilar cell with axon in the perforant pathway; and SS, hilar somatostatin cell with axon in the distal dendritic layer), as well as interneurons with both soma and axon in stratum moleculare (e.g., MOPP, moleculare cell with axon in the perforant pathway). In addition, mossy cells (MC) of the hilus constitute the excitatory commissural/associational input to the dentate granule cells.

Afferents (Inputs)

Cortical Afferents

The major cortical input to the hippocampal formation arises in layer II pyramidal cells of the entorhinal cortex (EC), projects

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through the angular bundle pathway, and enters the ipsilateral dentate gyrus via the perforant pathway.⁹⁴^,²³⁵ This excitatory input terminates largely on spines on the distal dendrites of granule cells (and on interneurons) in the outer two thirds of the dentate molecular layer (Fig. 3). The entorhinal input has been subdivided into two divisions, with fibers originating in the medial EC synapsing in the middle third of the molecular layer and fibers from the lateral EC synapsing in the outer third. Investigators continue to explore differential features of these subdivisions, some of which may be relevant to dentate seizure susceptibility. For example, the medial division is glutamatergic and evokes EPSPs with both NMDA and non-NMDA components; in the lateral division, opioid-dependent long-term potentiation²⁶ is supported by anatomically defined colocalization of glutamate and enkephalin, with the latter “transmitter” affecting regional interneurons (inhibition via μ- and δ-receptors) to mediate disinhibition of granule cells²⁶⁹—a perhaps critical step in dentate seizure genesis.

Anatomic studies of the EC projection to the hippocampal formation have also identified an input to hippocampus proper.

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This temporoammonic pathway arises in layer III cells of EC but separates from the perforant pathway to contact the most distal branches of pyramidal cells in the stratum lacunosum-moleculare of CA1 to CA3.²⁶⁴ Although clearly excitatory (i.e., glutamatergic), the functional nature of this pathway has been questioned because its influence on pyramidal cell discharge has been difficult to demonstrate.²²⁵ Recent experiments suggest that temporoammonic modulation of pyramidal cells is significant, and that this input may also differentially activate an interneuron subpopulation located in these distal reaches of the apical dendritic region (see Fig. 3).¹²³ It is worthwhile to note that the direction of input to cornu ammonis via this entorhinal input is opposite to that of the associational input via the major trisynaptic pathways; thus, pyramidal cell excitation and processing cannot be viewed as a one-way serial influence. The function of this pathway remains unclear but appears to provide a frequency-dependent modulatory action from the entorhinal cortex directly onto hippocampal pyramidal cells.¹⁰⁷

Subcortical Afferents

A variety of subcortical fiber inputs innervate the hippocampal formation, some in very specific laminar patterns and others in a more diffuse pattern (see Fig. 3). The major subcortical projections include:

The septohippocampal input arises in the medial septal nucleus and diagonal band of Broca and enters the hippocampus via the fimbria/fornix.²⁶⁸ This input provides the hippocampal formation with the vast majority of its acetylcholine (ACh)¹³¹ and comprises a subcomponent of the basal forebrain cholinergic projection to cortex that has been implicated in learning and cognitive function. However, it is now very clear that this input consists of both cholinergic and GABAergic components⁶; septohippocampal lesion experiments, designed to deprive hippocampus of its ACh supply, must be carefully interpreted in light of damage to both GABAergic and cholinergic inputs. Acetylcholinesterase staining, which disappears almost entirely with septal lesions or with fimbria/fornix transection, shows a discrete pattern of staining in all regions of hippocampus, with a concentration in thin supra- and subcellular regions (Fig. 3). Interestingly, recent studies suggest that some interneuron subpopulations are extremely sensitive to ACh¹⁹⁷ and may be excited at much lower thresholds than are the principal cells. This possibility is intriguing, inasmuch as at least one form of hippocampal θ-activity—the slow, rhythmic EEG activity that is associated with restful alertness—is mediated via cholinergic mechanisms¹²⁸ and may well depend on excitation of interneurons for synchronization of the hippocampal projection cell populations.²³⁷ The cholinergic synaptic action in hippocampus is primarily muscarinic (blocked by atropine). The GABAergic projection from septum to hippocampus appears to have a slightly different set of targets. Although it is difficult to identify the general pattern of septal GABA fiber ramification in hippocampus (because of the large intrinsic GABA network), tracing studies have shown that septohippocampal GABA fibers preferentially synapse on GABAergic basket cells in the dentate gyrus,⁶⁹ forming a pathway for hippocampal/dentate disinhibition.

The brainstem monoamine pathways also provide an important, presumably modulatory, influence on hippocampal neurons. Noradrenergic fibers arising from the locus coeruleus,¹³⁵ serotonergic fibers arising from the raphe nuclei,¹⁷⁰ and dopaminergic fibers (although very sparse) from brainstem nuclei have been shown to ramify diffusely within all regions of hippocampus. The noradrenergic input, although generally diffuse, is most obvious in the CA3 and dentate hilar regions. However, cells in all parts of hippocampus have been shown to be sensitive to norepinephrine (NE), primarily (but not exclusively) via a β-adrenergic receptor mechanism²¹⁷ that leads (via cyclic adenosine monophosphate [cAMP] production) to a blockade of a hyperpolarizing potential (with loss of spike-firing adaptation) and net cell excitation.¹⁴⁰ Norepinephrine has been implicated in a form of long-term potentiation (LTP) in the CA3 pyramidal cell region,⁹⁷ as well as in the dentate.²³² How these noradrenergic effects on hippocampal cells are related to whole-brain hyperexcitability is unclear because lesions of the ascending noradrenergic system yield a nervous system with heightened seizure susceptibility.¹⁵³ A mouse “knockout” of the norepinephrine-synthesizing enzyme (dopamine β-hydroxylase) also shows increased seizure susceptibility.²⁴⁴ In contrast to this net excitatory effect of NE in hippocampus, both serotonin 5-hydroxytryptamine (5-HT) and dopamine (DA) produce hyperpolarizing (inhibitory) responses in hippocampal pyramidal cells, mediated by G-protein–coupled mechanisms.⁹^,²² The role played by these potent modulators of cell excitability is yet to be well characterized. However, serotonergic fiber input, like the septal GABAergic input, has been recently traced to a specific contact with interneurons within the dentate hilus⁸⁷; specific serotonergic effects on interneurons may well be critical in the net influence of this pathway in hippocampus. Clearly, the effects of these monoaminergic afferents in hippocampus depend on the postsynaptic receptor subtypes upon which they synapse.¹⁰ Interneurons exhibit 5-HT3 receptors, which are colocalized with CB1 cannabinoid receptors, thus suggesting not only a specific serotonin modulation of interneurons, but also a complex interaction between 5-HT and the endocannabinoid system.¹⁷¹

Efferents (Outputs)

Cortical Projections.

The major hippocampal cortical efferents arise in the subiculum and CA1 regions and project to the lower layers of entorhinal cortex.²⁶⁵ This system completes a feedback loop to the EC (through hippocampus) (see Fig. 2), because the deep cortical layers of EC then influence the output of layers II and III projection cells.⁵ In addition, subicular fibers project to the perirhinal cortex, another component of the “parahippocampal” complex. Anatomic and electrophysiologic studies show that CA1 and subiculum send axons to widespread prefrontal cortices, including the prelimbic area, cingulate cortex, medial orbital cortex, and the infralimbic areas.¹⁰²^,¹⁸⁰^,²⁵⁸ Although the roles of these efferent projections have not yet been clearly understood, these connections are consistent with a role for parahippocampal and prefrontal cortices in cognitive processes. Further, because medial/orbital prefrontal regions have brainstem connections that modulate autonomic function, these hippocampal connections to prefrontal cortex may endow the hippocampus with a role in emotional and visceral aspects of behavior long associated with the limbic region.

Subcortical Projections.

The best studied of the subcortical hippocampal projections are the “reciprocal” connections from CA1 and subiculum back to the septum—but to the lateral, rather than medial, septal nucleus.²⁶⁵ Again, because the lateral septal nucleus connects closely with the medial septal nucleus (from which hippocampal afferents arise), this projection constitutes part of still another feedback loop between the hippocampus and a related structure (see Fig. 2). The nucleus accumbens of the basal forebrain is a related projection from the same general subregions of subiculum. This structure is associated with the “limbic” component of the ventral basal ganglia. The subiculum also provides important connections from the hippocampal formation to the thalamus (midline nuclei), amygdala, and hypothalamus (ventromedial nucleus and mamillary body).³⁷^,⁹³ Although these projections “make sense” in terms of the old Papez circuit view of limbic system involvement in emotional and visceral behaviors, the actual role of these efferents (and of the reciprocal connections

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to hippocampus, largely through septum) are still to be determined. One additional circuit of note includes the hippocampus as the component of the hypothalamic-pituitary-adrenal (HPA) axis.⁷⁶ Adrenal steroid receptor (glucocorticoid and, especially, mineralocorticoid) concentration is high in the hippocampus, and its modulation of hippocampal output may play a key role in controlling the release of corticotropin-releasing hormone (CRH) and in corticotropin release from hypothalamus (i.e., in feedback control of adrenal steroid secretion). The hippocampal efferents to hypothalamus may thus be critically involved in adrenal stress responses.²⁵³

Regional Characteristics

Dentate Gyrus.

The dentate gyrus is the primary target of cortical input to the hippocampal formation and consists of the granule cell region and the related dentate hilus. The granule cell region is neatly laminated,²³ with the granule cell bodies densely packed in stratum granulosum (SG) and their dendrites reaching through the stratum moleculare (SM) (see Fig. 3). The stratum moleculare is conventionally divided into thirds: The inner third is the focus of associational, commissural, and septal input; the middle third receives input from the medial EC; and the outer third receives input from the lateral EC. Partially surrounded by stratum granulosum is the hilus, home to a variety of polymorphic cells that include the excitatory (glutamatergic) mossy cells (primary source of the dentate commissural and associational connections) and inhibitory interneurons.⁴ Until recently, the dentate region of hippocampus was relatively neglected by epileptologists because it appeared to have a very high threshold for seizure activity.¹³⁸ Recent studies, however, have focused more closely on this region because (a) the granule cells are relatively resistant to seizure-associated damage²²⁴; (b) granule cell axons show a high degree of plasticity (sprouting) in epileptic brain⁴²; (c) changes in synaptic currents and voltage-dependent channels have been demonstrated in granule cells following kindling¹⁶⁵; and (d) maximal activation of this region is associated with the generalization of seizure activity through the limbic system and beyond.¹³⁸ Indeed, the dentate is now sometimes considered the gatekeeper of hippocampal excitability.⁹¹

Granule cells are unusual because they show constant turnover throughout life, regulated in part by adrenal steroids and stress,⁷⁵ exercise,¹¹² and even seizures.¹⁸³ The role of newborn granule cells has been discussed with respect to behavioral function,¹³² hippocampal repair,¹¹⁷ and development of the epileptic state.²⁰⁹ Electrical properties—intrinsic and synaptic—have been extensively studied,²¹¹^,²²⁷^,²⁵² and granule cells have been found to be rather unexcitable because they maintain a very negative resting potential. Prolonged depolarization also fails to evoke rapid, repetitive firing for long periods because these cells exhibit pronounced spike firing adaptation; bursts of action potentials are followed by a large after-hyperpolarization. Activation of EC afferents to the dentate evokes a monosynaptic EPSP in granule cells; it is unclear how much of this synaptic excitation in normal hippocampus is mediated by NMDA receptors.¹⁶⁵ In addition, this afferent input activates a powerful inhibitory local circuit that rapidly curtails granule cell firing.¹³⁸ As elsewhere in hippocampus, at least some of the dentate interneurons are activated at a much lower threshold than are the granule cells³⁰; activation of inhibitory interneurons dampens the granule cell discharge so that “physiologic” levels of EC input are likely to result in rather discrete and restricted dentate (i.e., granule cell spiking) output to the hilus and CA3. The granule cell axons (mossy fibers) excite hilar and CA3 neurons (both principal cells and interneurons) via glutamatergic mechanisms.²⁰⁶ These cells colocalize the opioid peptide dynorphin²⁵⁵ and contain a high concentration of zinc⁶⁸ in their terminals. Although the role of these colocalized substances remains controversial, evidence suggests that zinc may modulate synaptic plasticity (long-term potentiation [LTP]) at the postsynaptic cell¹³³; decrease glutamate release from the presynaptic terminal,¹² and even affect GABA receptors in epileptogenic circuits.⁴⁹^,¹⁶⁹ Further, it has recently been shown that granule cells/mossy fibers also contain and release GABA—an observation that has obvious implications for “excitatory” neurotransmission in the adult hippocampus and also for hippocampal development in the immature brain.⁸⁰

In addition to the granule cells, the other “projection” cell type in the dentate is the hilar mossy cell, which sends its axons into the inner SM, both ipsi- and contralaterally, to make excitatory connections on granule cell dendrites. These cells receive their primary input from granule cells (another feedback circuit) (see Fig. 2), although some mossy cells have dendrites that reach into the SM to receive EC input directly.²⁰⁵ Interestingly, mossy cells are among the most vulnerable cell types in the hippocampal formation, and their death is thought to trigger the granule cell axon sprouting response into the inner SM, often seen in epileptic hippocampus.⁴² It has also been hypothesized that mossy cell damage, by removing a tonic source of excitation to inhibitory interneurons, gives rise to disinhibition of the granule cells.²²² Recordings from mossy cells show them to receive a constant “spontaneous” stream of large, non-NMDA EPSPs²⁰⁶ from granule cell mossy fiber terminals that require minimal summation to trigger action potential discharge; thus, it is not surprising that mossy cells have a very low threshold for discharge and may fire in bursts of action potentials when the summed EPSP is very large.³² Recent studies have shown that mossy cells also receive input from CA3 projecting back into the hilus.²⁰⁷ Finally, it is of interest that these cells have none of the calcium binding proteins common in other hippocampal cell types (granule cells contain calbindin). It is thought that inadequate intracellular calcium buffering may contribute to mossy cell vulnerability, a possibility supported by the finding that the injection of an intracellular chelator will save these neurons from potentially toxic levels of excitation²¹⁰ and the apparent resistance to injury of calretinin-containing mossy cells in the mouse and the gerbil.⁷¹^,¹¹⁸

Local circuits in the dentate, once thought to be restricted to the relatively simple feedback loop between inhibitory basket cells and granule cells, are shown to be very complex (see Fig. 3). In addition to five subtypes of dentate basket cells,¹⁹⁹ the dentate contains a myriad of other GABAergic interneurons. Each subpopulation appears to have a specific dendritic and axonal arborization pattern,⁸⁹ and some colocalize (with GABA) peptide neurotransmitters. For example, the somatostatin-containing interneurons in the hilus send their axons into the outer molecular layer to interact with distal granule cell dendrites and with the incoming lateral perforant path fibers.¹³⁰ Although the role played by these interneurons is not yet clear, their mode of termination (and data regarding mechanism of action of somatostatin) suggests that they may have a presynaptic inhibitory function in relation to the perforant path input. Chandelier cells, a unique interneuron cell type, make exclusive—and apparently powerful—inhibitory synapses on the axon hillock and initial segment of hippocampal cells.³³^,²²⁶ Other inhibitory cell types have been described with specific axon terminal fields in the middle or inner SM,⁸⁹ and one interneuron cell type has now been found that projects to CA3 and CA1.³¹ Interestingly, all these interneurons appear to contain GABA; no excitatory “interneurons” have been described in the dentate (or anywhere else in hippocampus).

It is clear that each cell type has a special function, as determined by the arborization pattern of its dendritic tree, the localization of its axon terminals, and its colocalized transmitter content. However, because most interneurons synapse with each other, it is often difficult to predict what the net effect of activation of a given subpopulation might be; interneuron

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synapses directly onto granule cells may have a clear inhibitory outcome, but interneuron inhibition of interneurons may result in granule cell disinhibition or net excitation. Recent studies have revealed that at least one interneuron population in the dentate appears to be particularly sensitive to GABA_B receptor-mediated inhibition¹⁶⁴; it has been hypothesized that GABA_B receptors on the terminals of GABA interneurons may, in fact, regulate the cell’s release of GABA through a direct inhibitory effect by GABA on its own terminal.¹⁷³ Different interneurons, too, are differentially sensitive to excitotoxic damage; basket cells (at least those types that contain the calcium-binding protein parvalbumin) are resistant to damage,²²³ and are well preserved in epileptic hippocampus (even hippocampi showing severe mesial temporal sclerosis), whereas hilar somatostatin-containing interneurons are quite vulnerable (they lack calcium-binding proteins), and their loss may contribute to the hyperexcitability of dentate exposed to high levels of prolonged stimulation.⁵² Not surprisingly, the different subpopulations of interneurons express different receptor and channel combinations.⁴¹ Finally, in interneurons, as in other cells of hippocampus, activity-dependent (seizure-inducing) changes occur in cell properties (e.g., receptor complement, channels.¹⁸⁶ For example, neuropeptide Y (NPY) and associated receptors are dramatically regulated by seizure activity⁴⁶^,²⁵⁴; these changes, plus the observation that exogenously modified NPY expression may modify seizure activity, has led to the view that the NPY system constitutes an adaptive feedback system for regulating excitability.²⁵⁴

CA3.

The CA3 region is composed of large pyramidal cells (and associated interneurons) and is the recipient of mossy-fiber input from the granule cells. The region is conventionally divided into at least three divisions: CA3a (which we shall consider together with CA2 for the purposes of this discussion) is that part of the cell band most distal from the dentate (and closest to CA1); CA3b comprises the middle part of the band, nearest the fimbria/fornix connection; and CA3c is most proximal to the dentate, inserting into the hilus.⁵ Although each of these divisions may have slightly different characteristics, the region as a whole (including CA2) has been considered to be the “pacemaker” area of the hippocampus.²⁶⁷ In CA3 much of the rhythmic, synchronous bursting activity associated with interictal epileptiform activity appears to be generated. This population property is a product of the intrinsic properties of CA3 pyramidal cells and their high degree of excitatory collateral connectivity.²⁴⁹ Unlike other regions of the hippocampus, CA3 pyramidal cell axon collaterals ramify extensively within the local region and make excitatory contacts with their neighbors. The unique properties of CA3 local circuitry have been implicated in a number of hypotheses regarding learning and memory processes in the hippocampus,⁸¹ and also appear to provide a basis for oscillatory rhythms that are characteristic of hippocampus. The CA3 region (as well as entorhinal cortex) constitutes a generator of γ-frequency (10–30 Hz) oscillations, a cholinergically driven pattern that depends on coupling of interneurons (and pyramidal cell axons) via gap junctions, as well as via more conventional chemical excitatory (glutamatergic) and inhibitory (GABAergic) synapses.¹⁴⁶^,²⁵⁰ The CA3 region also generates sharp waves and high-frequency oscillations—EEG patterns implicated in memory consolidation.¹⁴²

Although the excitatory output of CA3 is often damped by strong inhibitory interneuronal influences, even minor reductions in inhibitory efficacy in CA3 can result in significant synchronized bursting, due to interaction among CA3 pyramidal cells. This bursting (or oscillatory drive) is relayed to the CA1 region ipsilaterally (via Schaffer collaterals) and to CA1 and CA3 regions contralaterally (the commissural fibers of hippocampus proper). Although this output is effective in driving postsynaptic targets, it also appears to be important in inhibiting the generation of ictal activities, particularly in entorhinal cortex.¹⁴ Because of the very extensive nature of the CA3 axon collateralization over the longitudinal extent of hippocampus,¹³⁴ there is significant divergence of this CA3 output (it is not laminar). Perhaps curiously, this same CA3 region is only reluctantly recruited into ictal-like seizure activity—perhaps because of the strength of its inhibitory circuitry or perhaps because the mechanism of the interictal-like bursts directly antagonizes seizure genesis.¹⁰⁴

The intrinsic and synaptic properties of CA3 pyramidal cells determine this unique set of epilepsy-related characteristics. Individual pyramidal cells in this region have an intrinsic burst propensity, apparently based on a relatively high density of calcium channels in their proximal dendrites.⁶⁶^,²⁶⁶ Membrane depolarization (e.g., from incoming synaptic activity) not only may trigger conventional sodium action potentials, but also may open these calcium channels; the calcium influx causes a more prolonged depolarization of the cell, driving additional action potentials in a “burst.” Because afferent input often involves activation of both excitatory and inhibitory influences onto CA3 cells, this burst propensity is generally curtailed by the hyperpolarizing effect of the inhibition.¹⁶³ When these bursts occur, however, they provide a potent drive, not only to CA1 targets, but also to neighboring CA3 cells (via the excitatory collateral system); a gradual recruitment of CA3 neuron activity can thus lead to synchronized burst discharge. Importantly, there also appears to be a very effective mechanism for turning off these bursts—the after-hyperpolarization generated by a calcium-dependent potassium conductance.⁹⁸ Thus, the very mechanism of burst generation—calcium influx—also involves a self-limiting process (the calcium-activated hyperpolarization). These processes presumably contribute to the reluctance of CA3 to participate in ictal-like activity, which requires prolonged depolarization and repetitive action potential discharge.

Presumably, the major trigger for CA3 discharge is afferent input from the dentate granule cells. Large mossy fiber terminals engage in very complex synapses on the proximal part of the CA3 apical dendrite in the stratum lucidum, where they contact complex dendritic spines; glutamate release from a single terminal evokes a large non–NMDA-mediated EPSP.²⁸ Fortunately, the baseline “spontaneous” level of granule cell activity is relatively low, so that CA3 cells are not constantly driven at high rates. The unique features of mossy fiber input appear to account for many of the region-specific properties of CA3. Mossy fibers colocalize glutamate with high concentrations of zinc (see earlier discussion), dynorphin, and GABA. Further, the mossy fiber terminals appear to have receptors for kainate (see next section), as well as for BDNF. BDNF application to the CA3 region results in synchronized burst discharge activity.²⁰⁸

Fortunately, the same mossy fiber input that activates CA3 pyramidal cells also drives local interneurons very effectively, so that CA3 cells are tonically inhibited by a variety of interneuron subtypes⁷⁹ (see Fig. 3). The subpopulations of interneurons in CA3 overlaps with, but is not exactly the same as, those in the dentate; basket cells provide potent inhibition to the level of the cell soma, and other cell types show unique dendritic arborization patterns and region-specific targeting by axon collateral. Investigators have shown that different morphologically defined interneurons also show different electrophysiologic properties; the interneurons include both fast-spiking cells—whose inhibitory postsynaptic potentials (IPSPs) summate to produce small, smooth IPSPs in pyramidal cells—and slow-spiking cells, which produce large, fast-rising IPSPs in the pyramidal cell target.¹⁶² As in the dentate, the dendritic region of CA3 is laminated; the most proximal apical dendrite receives mossy fibers exclusively, the mid-dendritic regions (strata radiatum on the apical side and oriens on the basal side) receive primarily associational and commissural fibers (i.e., from other CA3 cells),

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and the distal apical dendrites (stratum lacunosum-moleculare) receive input from the temporoammonic afferents (from EC) (Fig. 3). All these excitatory glutamatergic inputs are modulated not only by the local GABAergic circuits but also by the subcortical afferent systems. Interestingly, the mossy fiber input to CA3, because it is mediated by non-NMDA glutamate receptors, exhibits a different form of synaptic plasticity²⁵⁶ from the typical LTP (or long-term depression [LTD]) so intensively studied as a cellular model of learning (and a possible contributor to kindling). The plasticity of this synapse, in contrast to the LTP produced in stratum radiatum of the same region, appears to be particularly dependent on (sensitive to) monoaminergic activation of a cAMP second-messenger system.⁹⁷ Recent studies suggest that interneurons specific to the stratum lucidum are key participants in mossy fiber–induced synaptic plasticity.¹⁸⁴

Seizure-related pathology in the CA3 region tends to be rather varied.²²⁴ The neighboring CA2 transition zone, which does not receive mossy fiber input (and differs from CA3 in a few other subtle ways) is commonly identified as the “resistant sector” because these cells are sometimes the only CA pyramidal cells to survive in human TLE. Temporal lobe epilepsy-related “end-folium sclerosis,”¹⁴⁷ a variation on the mesial temporal sclerosis pattern, is a pathology that primarily affects the CA3 and hilar regions, leaving surviving neurons in the surrounding granule cell layer. The kainic acid [KA] model of TLE has been used to study this pattern of cell loss because intraventricular injection of KA produces excitotoxicity, primarily among CA3 pyramidal cells.¹⁷⁸ Studies have suggested that the KA receptors that mediate this damage are located on mossy fiber terminals; the excitotoxic effect of KA on CA3 cells is mediated indirectly by the KA-induced release of glutamate from these terminals. Indeed, if the granule cell input to CA3 is blocked (lesioned), the CA3 population is protected from KA damage.¹⁷⁷

CA1.

The CA1 pyramidal cells make up an apparently homogeneous population¹⁰³ which, together with their relatives in subiculum, comprise the primary output cells of the hippocampal formation. Their primary excitatory inputs are via the glutamatergic CA3 Schaffer collaterals (both ipsi- and contralateral), which contact spines on apical and basal dendrites in strata radiatum and oriens. An additional excitatory input (the strength of which is still unclear) is via the EC-originating temporoammonic system, which synapses in the distal apical dendrites in stratum lacunosum-moleculare.²²⁵ Although these CA1 pyramidal cells also receive inhibitory input from a variety of interneuronal influences,¹²² the strength of inhibition in CA1 seems lesser than that in dentate and CA3, and the cells, therefore, are more vulnerable to recruitment into seizurelike activity and to excitotoxic damage. This relatively low level of inhibition may also help explain why LTP is so easily induced in this region, compared with other brain regions.¹¹⁰^,¹⁴¹ Interestingly, unlike CA3, CA1 pyramidal cells appear to have relatively little excitatory interaction with each other,²⁴⁸ so the basis of their synchronization rests with CA3. In general, the cell properties and circuits intrinsic to CA1 are not themselves epileptogenic (i.e., these cells are not intrinsic “bursters”); however, once provoked or recruited (e.g., by excitatory drive from CA3), their control mechanisms are insufficient to prevent seizure activity from taking over the region. In mesial temporal sclerosis, CA1 (Sommer sector) is, next to the dentate hilus, the region showing most damage²⁶⁰—perhaps reflecting the inadequacy of CA1 control mechanisms to reduce cell excitation. Although it is clear that CA1 can easily be driven to seizure activity, it remains unclear what role this region plays in TLE—either its generation or maintenance—because these cells are often entirely absent from a hippocampus thought to be the source of seizure activity in TLE.

CA1 cell properties have been so intensively studied that CA1 cells are now often referred to as the “model” CNS neuron. A variety of voltage-dependent ion channels have been characterized in the CA1 pyramidal cell membrane, including high-threshold calcium currents²²⁷ (which are blocked by such drugs as nimodipine and nifedipine), a large number of potassium currents (delayed rectifier, calcium-activated, etc.), and even noninactivating sodium currents. These cells do not normally discharge in a burst pattern, but recent studies have shown that a subpopulation of CA1 cells tend to burst,¹⁰³ and that this proportion of cells increases as the extracellular potassium concentration increases—as might occur in epileptic tissue. Further, perhaps because of the relatively small extracellular space in CA1,²⁵¹ these pyramidal cells may be particularly sensitive to the effects of extracellular current flow as a source of ephaptic interaction and synchronization.²⁴⁶ A large number of recent studies have focused on the plasticity of receptors and channels in hippocampal CA1 pyramidal cells as a function of activity—both normal and pathologic.²¹^,⁴⁸^,¹⁰⁵ Such studies have illustrated the potential for epileptogenic stimuli to induce “channelopathies.”

The major basis for local circuit communication with the CA1 region lies in the interneuronal circuitry. In CA1, a number of different inhibitory (GABAergic) interneuronal cell types have been characterized, based on (a) the laminar location of the cell body (oriens, pyramidale, radiatum, lacunosum-moleculare); (b) the shape of the soma and the pattern of the dendritic ramification (which should provide some information about the source of inputs to these cells); (c) the “spininess” of the dendrites (many are aspinous); (d) the colocalization of transmitters/peptides with GABA (e.g., somatostatin, parvalbumin); and (e) regional specificity of its axon projection (basket cell specificity for CA1 somata, oriens/alveus cell projections to distal apical dendrites, etc.).¹²² Studies have suggested that a subpopulation of GABA neurons mediates GABA_B inhibitory effects²⁶³ and that different interneuron populations are differentially sensitive to ACh¹⁹⁷ and norepinephrine.⁵⁶ Of particular interest is the hypothesized role played by interneurons in the generation of the rhythmic activity that is so prominent in CA1 (e.g., θ-rhythm), especially within the context of theories in which these rhythms provide a framework for cognitive functions.²³⁷ Interneurons also appear to be the source (or target) of various modulatory substances that control hippocampal excitability, including opioids and endocannabinoids.⁴⁴^,⁸⁶^,¹⁶⁰ And recent studies implicate metabotropic glutamate receptor effects within the interneuronal circuitry as a particularly important new focus for understanding control of synaptic excitation and plasticity.⁹⁹^,¹²¹^,¹²⁴

This pattern of synaptic activities in CA1 has generated the most intense analysis, driven in large part by interest in the mechanisms of synaptic plasticity (LTP/LTD).¹⁴⁵ These studies have revealed that the EPSP in CA1 pyramidal cells has both NMDA and non-NMDA components; activation of the NMDA receptors is normally crucial for initiation of LTP-like events, but high levels of input, which activate high-threshold calcium currents, may also produce a form of LTP.⁷⁸ Studies have also confirmed the major role of intracellular calcium changes during synaptic plasticity, an issue that has been pursued with imaging techniques to follow localized changes in cellular calcium levels resulting from discrete synaptic inputs.¹⁹⁸ Also of considerable interest have been the studies of the various forms of inhibition in CA1 and their roles, not only in synaptic plasticity, but also in epileptogenicity. Investigators disagree about how activity-dependent changes in synaptic inhibition might occur but concur that plasticity is enhanced when inhibition is reduced. This finding is significant for epilepsy because reductions in inhibitory efficacy are clearly associated with the generation of seizure-like activity. The concept of the “dormant” or “disconnected” interneuron, originally developed within the context of epileptogenicity in the dentate gyrus, has also been found appropriate for the CA1

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region.²⁰ For example, in the KA model, CA1 becomes hyperexcitable when the CA3 region is damaged, and a reduction of both GABA_A and GABA_B IPSPs occurs; curiously, the GABA interneurons (and their connections) are still intact in this model, but appear to be more difficult to activate than in the normal brain (i.e., they act as though they are functionally “disconnected” from the target CA1 pyramidal cells).⁶⁷

Subiculum.

The subiculum has been studied primarily as the major output station for the hippocampal formation. As discussed above, it receives information from the CA1 region and relays the hippocampal output to cortical and subcortical sites. Despite this apparently pivotal role in the function of the hippocampal formation, the cellular and synaptic properties of subiculum have only recently received attention. This relative neglect is even more surprising within the context of TLE; in typical mesial temporal sclerosis (MTS), the greater portion of the CA1 region is damaged (leaving few viable CA1 cells) but the subiculum remains generally intact.¹¹^,²²⁴ Given the hypothesis that epileptic activity is generated within sclerotic hippocampus in TLE, and the knowledge that in typical MTS the CA1 region is damaged (or even absent), it may be that the subiculum is uniquely responsible for “projecting” the abnormal hippocampal output to other parts of the brain. How subiculum receives this abnormal hippocampal input in the face of CA1 destruction, and how it processes/modulates such excitability before sending it on to EC, prefrontal cortex, midline and anterior thalamus, amygdala, and hypothalamus remains unexplored. A number of relatively recent studies have begun to fill in the void on subiculum function, both within the context of normal “hippocampal” function,¹⁷⁶ and as seen within the epileptic brain.¹¹⁹^,²³⁰

What little we do know about subiculum comes from recent studies of the intrinsic and synaptic properties of subicular neurons.¹⁴⁸^,²⁴⁰^,²⁴⁵ These investigations suggest that subicular projection cells are similar to hippocampal pyramidal cells in CA1 (and CA3). Subicular pyramidal cells appear to be grouped into two categories; one category comprises cells that normally produce burst discharges (similar to CA3), and the other category consists of “regular” firing cells (like most CA1 cells). Both types receive input from CA1 and project to EC. EPSPs with both NMDA and non-NMDA components, and complex GABAergic IPSPs, can be recorded in these cells. The mechanism of discharge in the bursting neurons appears to involve a calcium current (as in CA3 pyramidal cells); however, there is also a tendency toward burst discharge when the cell recovers from a hyperpolarizing drive (similar to the low-threshold burst seen in thalamic neurons), and the underlying basis for that burst may be activation of a low-threshold sodium current. Finally, these cells show a pronounced inward rectifier current (even more so than that in CA1) that provides a depolarizing influence on the cell when it is hyperpolarized. These characteristics would, in theory, endow the subicular neuron with the ability to support hyperexcitable, burst-like discharge generated within an abnormal hippocampus. Because so little is known about the local circuitry of the region, it remains unclear to what extent subiculum might be capable of independent epileptogenesis (e.g., when deafferentated from CA1 and CA3 in MTS).

Entorhinal Cortex

The entorhinal cortex is a relatively large area that interfaces anatomically with the hippocampus so strongly that Ramon y Cajal¹⁹⁶ suggested a functional solidarity between the two structures. Even today, much effort is focused on dissociating the functions of the two structures, compared with the surrounding (parahippocampal) cortical tissues. It is clear that both the hippocampus and entorhinal cortex provide modulation of many functions, particularly those associated with the declarative forms of memory.²⁷²

Anatomically, large portions of the neocortex project directly to the entorhinal cortex¹⁰⁰ and to its dorsally adjacent neighbor, the perirhinal cortex.³⁶^,³⁷^,⁵¹ The hippocampus receives most of its cortical information from these two structures. The anterior cortical projections to the entorhinal cortex are particularly dense from the infralimbic and the orbitofrontal cortices, areas that are prominent in stimulus–reward associations and other goal-directed responses.⁴⁰ Posteriorly, the orbitofrontal cortex blends first into the insular cortex, where gustatory information is processed, then into the perirhinal cortex, the functions of which are currently under study because of its role in temporal lobe amnesia²⁷³ and its ability to propagate convulsive seizures.⁹⁵ Both of these two cortical areas, in turn, densely innervate the entorhinal cortex.³⁷ The cingulate cortex also innervates the entorhinal cortex,¹¹³ and its loss significantly affects memory, especially in delayed response tasks.⁶⁰ Lastly, the subiculum interfaces between the hippocampus and the entorhinal cortex¹⁷⁵ and provides dense projections to both the medial entorhinal area and the perirhinal cortex.¹¹⁴^,²⁶⁵ Based on the intrinsic “burst firing” properties of many of these subicular cells,²⁴⁰ it is presumed that they provide a strong amplifying function for information to and from the hippocampus and entorhinal cortex.

The subcortical inputs to the entorhinal cortex are numerous. Prominent in this regard are several olfactory structures, including a massive input from the olfactory bulbs, which innervates the superficial layers of the entorhinal cortex, along with dense projections from all the olfactory or piriform cortex.⁸² Clearly, the entorhinal cortex is privy to considerable olfactory information. Also, projecting strongly to the entorhinal cortex are the cholinergic fibers from the medial septum. It is presumed that, because these same cholinergic cells drive the rhythmic θ-activity pattern in the hippocampus associated with memory storage, the entorhinal activity contributes importantly to this process.³ Emotionally colored information readily arises from the amygdala, where projections are derived from the cortical nucleus to both the medial and lateral entorhinal cortex, and the basolateral and lateral amygdala nuclei to the lateral entorhinal cortex.¹⁸^,¹⁸⁷ From the brainstem, serotonergic afferents originate in the raphe nuclei, and noradrenergic inputs arrive from the locus coeruleus and the reticular tegmental area. Additionally, thalamic afferents to the entorhinal cortex originate in the reuniens nuclei and in the anterior thalamic nuclei.¹⁶ Thus, the entorhinal area is broadly innervated by both cortical and subcortical structures, and clearly participates in a variety of behaviors, particularly those involving learning and memory.

Like other periallocortical and isocortical structures, the entorhinal cortex is composed of six layers, including a superficial layer I, which is comprised largely of afferents onto the apical dendrites of the cells in layers II–VI.⁵⁴^,²⁶⁵ Its intrinsic organization is realized by prominent longitudinal pathways, much like the association pathways in the piriform cortex, with caudal levels projecting most strongly to rostral levels. Within each entorhinal area (medial and lateral), the deeper layers innervate the more superficial layers, and the superficial layers innervate other superficial layers in adjacent areas. In this regard, the entorhinal pyramidal cells of layer V receive strong input from the perirhinal cortex and the sensory cortices²⁵ and, in turn, project to the superficial entorhinal layer II and III cells.⁵⁸ In addition, the layer V entorhinal cells show strong interconnections via recurrent excitatory synapses, much like the CA3 cells in the hippocampus and, when appropriately provoked, are capable of firing in burst patterns.²³⁶ This disposition clearly is important for epilepsy. Connections between the medial and lateral entorhinal areas are more sparse than their longitudinal associations and largely involve diffuse projections that arise

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from the medial entorhinal cortex and project to the lateral entorhinal cortex.⁵⁴ These medial-to-lateral projections are not reciprocal.²⁶⁵

The output of the entorhinal cortex to other cortical and subcortical structures is largely reciprocal with the inputs described. However, the outputs generally arise from the deeper layers (IV–VI), whereas inputs are received in the superficial layers (I–III). Thus, the entorhinal cortex innervates the olfactory and visual cortices, as well as the amygdala, septum, and thalamus, including the anterior, reuniens, pulvinar, and several “auditory” thalamic nuclei. The other major output of the entorhinal cortex is to the hippocampal formation. Here, the layer II entorhinal cells project to the dentate gyrus and to the CA3 cell field, constituting the well-known “perforant pathway,” whereas the layer III cells give rise to fibers that innervate the CA1 field. These two entorhinal outputs provide the hippocampus with much of its cortical information.⁵⁵

In comparative studies, clear species differences are apparent in cortical connections with the entorhinal cortex. In the rat and cat, a very large reciprocal connection exists between the entorhinal cortex and the olfactory system, a connection that is much reduced in the primate. By contrast, the primate shows highly differentiated connections between multimodal parasensory and paralimbic cortices and the entorhinal cortex, which are not so evident in the rat and cat.²⁰² Also, the subiculum in both humans and other primates is considerably larger than that of other species. Perhaps, with such an increase in the size of the primate subiculum, its effect on the entorhinal cortex is enhanced proportionately.

Although the cells that comprise the entorhinal cortex are of mixed types, the majority are pyramidal in shape. Based on their intrinsic properties, most (>90%) of the layer V cells are “regular spiking,” like most other neocortical neurons,⁴⁷ with only a few “burst-firing” cells and a few “fast-spiking” or presumed inhibitory interneurons.⁸⁸^,¹⁰⁸ Although many of these layer V cells provide important communication routes outside the entorhinal area, the best known entorhinal output, as described earlier, is the perforant pathway. The latter originates in both the medial and lateral entorhinal areas from either “stellate” (layer II) or small pyramidal (layer III) cells. Both of these pathways stain intensely for heavy metals using the Timm method, and they appear to use glutamate as their principal excitatory transmitter.²⁴¹ Indeed, both the superficial layers and the deep layers of the entorhinal cortex have many cells that possess glutamate receptors of both the NMDA and non-NMDA types, and repetitive stimulation at higher frequencies (as in kindling) appears to unmask depolarizing NMDA receptor-dependent responses easily, particularly in the superficial layers.⁹² With this in mind, in temporal lobe tissue excised from TLE patients, an increase in excitatory amino acid receptors in the parahippocampal gyrus has been reported.⁷² This increased expression of excitatory receptors could easily reflect much of the hyperexcitability characteristic of that TLE tissue.

Also prominent in the entorhinal cortex is the inhibitory transmitter GABA. Although the deep entorhinal cells show little evidence of slow GABAergic IPSPs, and their fast IPSPs are weak,⁹² GABA is strong in superficial layers.¹⁰⁶ In addition, GABA antagonists applied to slices of the entorhinal cortex result in large paroxysmal depolarizations, often lasting hundreds of milliseconds; in contrast, the same treatment of the hippocampus produces a disinhibited response of only 100 msec or less. Importantly, the disinhibited entorhinal cortex response in the presence of GABA antagonists is much smaller than that arising during exposure to low extracellular Mg²⁺.

In a horizontal slice preparation containing both entorhinal cortex and hippocampus, tissue exposure to low Mg²⁺ results in the development of protracted seizure-like events that share ionic properties with in vivo preparations. For example, the increases in [K⁺]_O in the slices during “seizures” are similar in intact animals,²³¹ with the larger increases occurring in the deeper layers. This large response in deep layers likely results from the seizure activity induced in the highly interconnected layer V pyramidal cells. During the seizure, much smaller increases in [K⁺]_O are associated with the superficial layers of the entorhinal cortex. In a similar manner, the seizure-inducing effects of low Mg²⁺ can be duplicated in the slice preparation by experimental elevation of [K⁺]_O. This manipulation results in low-threshold burst responses in the entorhinal cortex, which are often independent of the hippocampal burst response.¹⁷

In the low-Mg²⁺ slice preparation, after about an hour of large-amplitude and long-duration depolarizations, the discharges change quite suddenly into shorter events. At this time, the events become synchronized throughout the various cortical structures in the slice and exhibit features similar to the late stages of status epilepticus in humans.⁵⁷ This change in recurrent discharges from an early to a late form can be blocked by increases in GABAergic activity or can be hastened by GABA antagonists. This finding suggests that reduced efficiency in GABAergic communication may underwrite the transition in the seizure discharges from an early to a late form.

It is important to note that, in low Mg²⁺ conditions, the early form of the entorhinal seizures responds well to therapeutically relevant doses of several different anticonvulsants. However, the late form of the entorhinal discharge is unresponsive to any of the clinically used anticonvulsants, similar to status epilepticus in humans; this property of the entorhinal model system may provide a means of testing agents for their therapeutic efficacy against drug-resistant seizures.⁹² It is also apparent that the intrinsic and synaptic properties of the entorhinal cortex significantly contribute to the development of these drug-resistant epileptiform responses. For example, in this model system, the synaptic activation of the dentate gyrus is quite weak and rarely produces action potentials. Thus, it appears that the dentate gyrus filters both epileptic activity¹⁰⁹ and normal information,⁷⁷ while the CA3 cells impose an interictal profile on the network that suppresses ictal events.¹³ However, with sufficient alterations to the entorhinal/hippocampal network, the dentate gyrus loses some of its filter function and begins to augment synchronized discharges, reinforcing rather than dampening abnormal activity in the entorhinal/hippocampal loop.¹³⁸ Such alterations in function would surely be associated with impairments in the normal behavior supported by this network.

Perirhinal Cortex

Lately, there has been considerable interest in the perirhinal cortex. This interest arises largely from the finding in the monkey that many of the symptoms of human temporal lobe amnesia are duplicated by perirhinal cortex lesions.²⁷⁴ Spontaneous activity in the perirhinal cortex also is uniquely tied to the entorhinal cortex, which suggests a close relationship between it and the entorhinal–hippocampal system that is not evident in other neocortical systems.⁴⁵ This relationship also exists at the behavioral level, at which spatial learning can be impacted in perirhinal lesions much like that seen after hippocampal lesions.² In addition, in the context of epilepsy, it has been shown recently that kindling of the perirhinal cortex provides the fastest rates of epileptogenesis in the forebrain, accompanied by extremely fast convulsion onset latencies (usually <1 sec). Both the rapid genesis of these kindled seizures and their brief latencies to motor expression suggest that the perirhinal cortex¹⁵⁴^,²⁰³ and the adjacent insular cortex¹⁶⁸ must be intimately connected with motor areas that support convulsive expression.

Positioned laterally adjacent to the entorhinal cortex, the perirhinal cortex extends from the posterior margin of the

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entorhinal area forward to the insular cortex.³⁶^,³⁷ Throughout its course, it forms the banks of the rhinal sulcus. The perirhinal cortex is richly innervated by cortical afferents that arise from the frontal, temporal, parietal, occipital, and piriform cortices.⁵¹^,²⁴² Further, the subcortical afferents include the thalamus (reuniens, posterior and “acoustic thalamus”), lateral nucleus of the amygdala, claustrum, endopiriform nucleus, and dorsal raphe nuclei.¹⁸⁷ Although less is known about the projections of the perirhinal cortex, its efferents to the cortex tend to be reciprocal with the afferents indicated above.²⁶⁵ In considering its rapid kindling rates, the dense projection from the anterior perirhinal area to the frontal motor cortex is particularly intriguing.¹⁵⁵ Subcortical efferents of importance include the thalamus (nucleus reuniens, posterior and acoustic thalamus), basolateral and lateral amygdala, and nucleus accumbens.⁷⁰^,¹⁵⁵^,²²⁰^,²⁶⁵

There has been little study of the intrinsic organization of the perirhinal cortex. Cytoarchitectonically, it is agranular cortex, largely devoid of layer IV. The general excitability of the perirhinal cortex appears to parallel that of the entorhinal cortex, and indeed, there exist strong anatomical and physiological (excitatory) interactions between them.⁵³ With depolarizing current injection into perirhinal cells at their resting potential, most layer III pyramidal cells show regular spiking features. However, like the cells of the somatosensory and visual cortices,⁴³ intracellular depolarizing current into resting layer V pyramidal cells provokes burst discharges, which transform into a single-spiking profile when their membrane is held at more depolarized values.⁶⁵^,¹⁷⁴ Importantly, these bursting layer V perirhinal cells project densely to the frontal motor cortex.¹⁵⁶ By contrast, layer VI cells are mostly late-spiking in character, including both pyramidal and nonpyramidal cells, and are unlike any other cortical region studied to date. Recently, it has been shown that loss of the perirhinal cortex (in combination with the piriform cortex) prevents the normal development of clonic motor seizures during dorsal hippocampal kindling.¹¹¹ Similarly, extensive perirhinal/insular lesions³⁵ or chemical insular suppression alone,¹¹⁶ but not discrete perirhinal cortex lesions alone,²¹² significantly delays amygdala kindling. Thus, perhaps it is recruitment of the perirhinal/insular efferents during kindling or other forms of epileptogenesis that carries focal, mesial-limbic seizures into their generalized convulsive form. This result is clearly suggested by the recent studies of Harvey and Sloviter,⁹⁰ in which the electrographic activity and c-fos expression associated with the spontaneous seizures that occur weeks after exposure to pilocarpine-induced status epilepticus begins outside the hippocampus in parahippocampal structures like the perirhinal cortex.

Piriform or Olfactory Cortex

The piriform cortex is continuous with the entorhinal cortex anteriorly and with the perirhinal cortex ventrally (rat) or medially (cat, primate). The critical importance of the piriform cortex and the other olfactory structures for survival and reproduction in macrosomatic animals is reflected by their relatively large size. By comparison, in humans, dependency on olfactory information has been reduced considerably, along with the size of the olfactory structures, including the piriform cortex. Yet, despite its relative diminution in humans, activation of the olfactory system creates memories that are vivid and enduring, and likely provide the distinct olfactory auras experienced by some TLE patients.

The intrinsic organization of the piriform cortex involves three basic layers: The superficial plexiform layer (layer I), the cell-dense somatic or pyramidal cell layer (layer II), and the deep, diffuse polymorphic cell layer (layer III). As with the entorhinal and perirhinal cortices, layer I consists primarily of afferent inputs to the apical dendrites of deeper cells. In addition, layer I has been subdivided into layers Ia and Ib, each containing its own afferents. Layer II is densely packed with pyramidal and semilunar cells, whereas layer III contains mostly pyramidal cells in its superficial part and nonpyramidal cells in the deeper part. Many of these deep, nonpyramidal cells are presumed inhibitory interneurons and likely provide the strong recurrent inhibition shown by the piriform cortex.⁸²

Fibers arising from the olfactory bulbs comprise the primary input to the piriform cortex, where they heavily innervate distal dendrites in layer Ia. Other important inputs to the piriform cortex include the anterior olfactory nucleus (to layer Ib), ventral tenia tecta (to layers II and Ib), nucleus of the lateral olfactory tract (to layer II), cortical nucleus of the amygdala (to all layers), and the insular cortex (to layer III).¹⁹^,⁸⁵ Deep to layer III of the piriform cortex and laterally adjacent to the amygdala is the endopiriform nucleus. This relatively long and highly excitable structure provides dense innervation to layer Ib of the piriform cortex throughout its anterior-posterior extent.⁸²

Subcortical inputs to the piriform cortex include the anterior amygdala area, substantia innominata, midline thalamus, and most of the hypothalamus. The brainstem afferents come from the dopaminergic cells in the ventral tegmental area and substantia nigra, the noradrenergic cells from the locus coeruleus, and the serotonergic cells from the raphe nuclei.²⁴³ These brainstem afferents tend to distribute broadly in all three cell layers.

The network organization of the piriform cortex involves both vertical and horizontal dimensions. In the vertical domain, a precise ordering of fibers is present, best characterized by the segregation of afferents to the superficial layer Ia and the association fiber system to layer Ib. There is further segregation of the association fibers, in that those arising in the anterior piriform, usually from layer II, innervate the more superficial parts of the posterior piriform Ib, whereas the association fibers arising from the posterior piriform cortex do so from layer III alone and innervate the deeper part of anterior Ib.

In addition, the organization of the olfactory system is both divergent and convergent, so that activation of restricted parts of the olfactory bulb will broadly innervate the entire superficial piriform cortex, whereas inputs from all parts of the olfactory bulb will converge on discrete areas in the piriform cortex. To achieve the divergent innervation, it has been shown that a single piriform association fiber will course longitudinally for a considerable distance, making only a few contacts but with many neurons.⁸⁴ The epileptic disposition of this network of cells has been studied extensively by Haberly and colleagues, particularly with current source density analysis, and presently is a favorite structure for network modelers interested in learning and memory.¹⁵^,⁸³

In interfacing with several other olfactory structures, the output of the piriform cortex remains relatively restricted to much of its own association network. However, it does project densely to adjacent cortical structures, including the insular, perirhinal, and entorhinal cortices, as well as to a few subcortical structures, such as the lateral hypothalamus, ventral striatum, and dorsal medial thalamic nucleus.⁸⁵

The importance of the piriform cortex as a seizure generator is evident in a variety of whole-animal experiments. Until superseded recently by the perirhinal and insular cortices,¹⁵⁴^,¹⁶⁸ the piriform cortex was thought to develop kindled seizures faster than any other structure in the forebrain.¹³⁶^,¹⁵⁶

During kindling, the piriform cortex develops interictal spikes before all other limbic structures; when the interictal spikes are present concurrently in several structures, spikes in the piriform cortex anticipate spikes in the other structures.¹⁹¹

In the deep layers of the anterior piriform cortex, in or near the endopiriform nucleus, picomolar amounts of several convulsants (including GABA antagonists and cholinergic and

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glutamate agonists) have been reported to induce the rapid development of convulsive seizures.¹⁸⁸ Such pharmacologic sensitivity has not been observed elsewhere in the brain. A second, central area in the piriform cortex, transitional between anterior and posterior regions, provides dense expression of GABAergic neurons that are believed to broadly modulate excitability of this entire area.¹³⁷ When damaged, this expression results in facilitated kindling from the adjacent amygdala.²¹³

The sensitivity of the piriform cortex to seizure activity is highlighted by its extreme vulnerability to protracted seizures. In several models of status epilepticus, the piriform cortex is the first structure to experience damage, an effect that is massive.¹⁷⁹

The plasticity of the piriform cortex also has been demonstrated using in vitro experiments. In tissue slices taken from previously amygdala-kindled rats, excitability in the piriform cortex is clearly enhanced.¹⁵⁸ A parallel enhancement in piriform excitability is observed in control tissue when it was returned to normal Mg²⁺ perfusate after previous exposure to the seizure-inducing effects of low Mg²⁺. The earlier exposure to low Mg²⁺ irreversibly increases piriform excitability for synaptically triggered network events mediated by changes in the deep layer III cells,⁹⁶ as well as for spontaneous events.¹⁵⁷ Such changes in the piriform cortex could provide the basis for alterations in olfactory experience and memories. Clearly, the powerful association system in the piriform cortex, coupled with its rich interconnections to the entorhinal and perirhinal cortices, provides it with the capability to trigger and amplify epileptic events.

Amygdala

The amygdala complex plays an important role in a variety of behaviors, including fear, aggression, learning, reproduction, and epilepsy.¹^,⁷⁴ Until recently, its connections with the hypothalamus were considered to be central to the expression of most of these behaviors, but it is now believed that many are realized through its connections with the sensory systems, cortex, striatum, and brainstem.⁵⁰

The amygdala is a heterogeneous collection of nuclear groups,¹⁵⁰ often divided simplistically into the following divisions: The olfactory group, including the anterior area, nucleus of the lateral olfactory tract, and the cortical nucleus; the central-medial group, including the central and medial amygdala nuclei; and the basolateral group, including the lateral, basolateral, and basomedial nuclei. Not surprising, such a heterogeneous structure is matched equally by a diversity of connections.

The afferents to the olfactory group include both the olfactory bulbs and a third-order olfactory input via the piriform cortex.⁸⁵ The hippocampus provides some direct input to this group from CA1 but has more indirect influences through the subiculum and tenia tecta.¹⁸¹ Important innervation also comes from the lateral entorhinal and agranular insular cortices. Subcortical afferents include cholinergic projections from the diagonal band, noradrenergic fibers from the locus coeruleus, and serotonergic fibers from the raphe nuclei.⁶⁴ Other important afferents involve the highly excitable endopiriform nucleus and several hypothalamic and thalamic nuclei.

The efferents of the olfactory group are largely reciprocal with their afferents. However, other important targets include the ventral striatum, which gives strong motor representation to the olfactory group output, and the nucleus accumbens, where reward mechanisms are influenced. This group also is well connected with the other amygdala nuclei, particularly the medial, central, and basolateral nuclei, but not with the lateral nucleus.⁵⁰

In the medial-central group, the medial nucleus is reached by several cortical afferents, including those from piriform, agranular insular, retrosplenial, and entorhinal cortices, as well as by fibers from the subiculum and hippocampus.¹⁴⁹^,¹⁸¹ Subcortical afferents arise from the hypothalamus and several midline thalamic nuclei, as well as from the brainstem structures described for the olfactory group. Efferents of the medial nucleus that might be important for epilepsy project to the entorhinal cortex and ventral striatum.¹⁸ The hypothalamus and the brainstem also receive many efferents from the medial nucleus.⁵⁰ Although cells in the medial nucleus express many peptides such as cholecystokinin (CCK), vasoactive intestinal polypeptide (VIP), enkephalin, somatostatin, thyrotropin releasing hormone, and others, GABA is the transmitter that is particularly well represented. Perhaps this is why the medial nucleus is the slowest of the amygdala nuclei to develop kindled convulsions.¹²⁷

By contrast, the central nucleus is the fastest nucleus to kindle.¹²⁷^,¹⁶⁷ This nucleus receives afferents from the piriform, agranular insular, entorhinal, perirhinal, and other cortices.⁵⁰ Hypothalamic afferents innervate the central nucleus, as do extensive inputs from a variety of thalamic nuclei. As with the other amygdala groups, brainstem afferents contain nor-adrenergic and serotonergic fibers. The cortical efferents from this group are Spartan, except for those to the perirhinal cortex.⁵¹ This projection may have important implications for the generation of convulsive seizures, because the fast-kindling central nucleus is second only to the faster-kindling perirhinal cortex.¹⁵⁴ Important subcortical efferents include projections to the medial dorsal striatum, fundus striati, and hypothalamus.⁵⁰ Brainstem communication involves the central gray, pedunculopontine nucleus, parabrachial nucleus, nucleus of the solitary tract, dorsal motor nucleus of the vagus, and others. These brainstem structures provide considerable motor and autonomic nervous system expression for the central nucleus. Although the number of neuropeptides observed in this nucleus exceeds all others, the manner in which they contribute to the excitability of the central nucleus has not been determined.

Simplistically, the basolateral group comprises the basolateral, basomedial, and lateral amygdala nuclei. This group is distinguished by its dense connections with the neocortex, originating in the piriform, entorhinal, agranular insular, infralimbic, cingulate, orbitofrontal, and perirhinal cortices.¹⁴³^,¹⁴⁴^,¹⁸⁹^,¹⁹⁰^,²³⁴ Subcortical afferents of importance include the dense cholinergic projections from the diagonal band, ventral pallidum, and substantia innominata. Further afferents reach the basolateral group from the hypothalamus and several midline thalamic structures, as well as from dopaminergic, noradrenergic, and serotonergic fibers from the brainstem.

The cortical outputs of the basolateral group are largely reciprocal with the inputs described, with the addition of a dense projection to both the somatosensory and motor cortices. The subcortical efferents of this group include projections to the dorsal and ventral striatum, as well as the nucleus accumbens and olfactory tubercle. Whereas much of the hypothalamus receives efferents from the basolateral group, projections to the thalamus are restricted to the dorsomedial nucleus.¹²⁰ Unlike the central nucleus, the basolateral group also shows limited innervation of the brainstem.

The diversity of transmitters seen in the other amygdala groups is not evident in the basolateral complex. Of course, the basolateral complex still exhibits many peptides and is highly sensitive to the classic transmitters. Indeed, most of the in vitro electrophysiologic studies of the amygdala have involved the basolateral nucleus. In this regard, it has been shown by Rainnie and colleagues¹⁹²^,¹⁹³^,¹⁹⁴^,¹⁹⁵ that: (a) low Mg²⁺ perfusion of the amygdala-piriform slice preparation readily results in spontaneous interictal and ictal burst discharges in the basolateral amygdala that are both NMDA- and non–NMDA-sensitive; (b) GABAergic inhibition is feed-forward to this group via the stria terminalis and direct via the lateral amygdala; and (c) previous

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kindling of the amygdala results in a loss of only the stria-mediated GABAergic inhibition and is accompanied by the development of NMDA-sensitive, spontaneous burst discharges. Many of these changes in kindled tissue are evident similarly in the adjacent piriform cortex.⁹⁵^,¹⁵⁸ Thus, it appears that the development of epileptiform discharges in the amygdala-piriform area is associated with an increased sensitivity of both NMDA and non-NMDA glutamate receptors and with the loss of some GABAergic inhibition. Finally, although the basolateral nucleus is undistinguished in its kindling profile, developing convulsions at a rate intermediate between the fast-kindling central nucleus and the slow-kindling medial nucleus, it plays a critical role in the development and maintenance of limbic-based status epilepticus.²⁵⁷

When examining the amygdala in an interactive context, by comparing its kindling progression against other limbic or cortical structures concurrently stimulated by alternating between the amygdala and those other sites, an antagonism between the sites in their kindling progression becomes evident.³⁴^,⁵⁹ The amygdala kindling dominates in paired encounters with the septum, ventral hippocampus, piriform or posterior perirhinal cortices, but loses and remains undeveloped in the presence of concurrent stimulation applied to either the anterior perirhinal, insular or anterior cingulate cortices.³⁴^,¹⁶⁶ Clearly many dynamic interactions can be provoked in the limbic system, which can favor or disfavor epileptogenesis, depending upon their origins and timing.

Summary and Conclusions

Although Broca’s²⁷ first description of the “limbic brain” was based on strictly anatomic contiguity, the idea of a limbic “system” has proved very resilient, even in an age of functional emphasis. Papez¹⁸² painted a picture of strong connectivity among various elements of the limbic brain, giving rise to a system in which sensory, endocrine, and autonomic functions were integrated to produce complex emotional behaviors. In Maclean’s¹³⁹ reinterpretation of the field, the limbic brain stood interposed between the older parts of the CNS (dealing with sensing of the “inner world”) and the newer parts of the CNS (providing sensory experience of the external world). Behavioral studies on monkeys¹¹⁶ and on epilepsy patients with bilateral temporal lobe removals²¹⁶ showed this integrative system to be important in memory, as well as in emotional behaviors. These views have continued to receive support from recent studies. Many modern investigators have taken issue with the concept of a single limbic system involved in so many different (and such diverse) functions. Yet the richness of anatomic connectivity among many of these limbic brain regions and the relatedness of many of the implicated behaviors argue for some significant level of interaction among putative limbic structures.

This chapter has concentrated on a few of the most salient “stations” in the limbic complex—salient, at least, with respect to what we know about epileptogenesis. Our omission of the hypothalamus, limbic aspects of the basal ganglia/thalamic complex, limbic (cingulate) cortex, and septal and olfactory regions from this discussion says less about their involvement in epileptogenesis than about our lack of understanding of their structure and function. Without question, however, the hippocampus, entorhinal cortex, amygdala, parahippocampal/piriform cortex, and perirhinal cortex are major players in complex partial or temporal lobe seizure syndromes. These regions display relatively low thresholds for seizure induction, tend to show some degree of damage associated with long-term (continuous) seizure activity, and are intimately connected. Seizure initiation at one site may spread rapidly to related structures. Disruption of one (or more) region—e.g., in temporal lobectomy—will inevitably have consequences for function and excitability in the remaining cortices. The view of each region as an isolated entity was initially useful in attempts to characterize these structures but must be ultimately misleading with respect to both normal function and generation (initiation, maintenance) of epileptic activities. Despite the difficulties in defining a “limbic system,” it is perhaps our inability to view these structures within the context of an interactive “system” that has made it so difficult to identify the epileptogenic keys to limbic structure and function.

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	Epilepsy: A Comprehensive Textbook 2nd Edition
	© 2008 Lippincott Williams & Wilkins

Epilepsy: A Comprehensive Textbook2nd Edition

Epilepsy: A Comprehensive Textbook
2nd Edition