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Epilepsy & Behavior 7 (2005) 390–400 www.elsevier.com/locate/yebeh

Review

Axonal sprouting of GABAergic interneurons in temporal lobe epilepsy Suzanne B. Bausch * Department of Pharmacology, Program in Neuroscience, Uniformed Services University, Room C2007, 4301 Jones Bridge Road, Bethesda, MD 20814, USA Received 15 July 2005; accepted 23 July 2005 Available online 27 September 2005

Abstract Temporal lobe epilepsy is one of the most common forms of epilepsy. Numerous contributing factors and compensatory mechanisms have been associated with temporal lobe epilepsy. One feature found in both humans and animal models is sprouting of hippocampal principal cell axons, which suggests that axonal sprouting may be a general phenomenon associated with temporal lobe epilepsy. This article highlights the evidence showing that hippocampal GABAergic interneurons also undergo axonal sprouting in temporal lobe epilepsy. The caveats and unanswered questions associated with the current data and the potential physiological consequences of reorganizations in GABAergic circuits are discussed. Published by Elsevier Inc. Keywords: Dentate gyrus; Hippocampus; Inhibition; Neuropeptide; Calcium-binding protein; GABA; Temporal lobe epilepsy

1. Introduction Temporal lobe epilepsy is one of the most common forms of epilepsy [1–5]. Otherwise healthy individuals can acquire temporal lobe epilepsy as the consequence of brain insults such as stroke, trauma, and neurodegenerative disease. Development of acquired epilepsy is typically delayed by months or years from the initial neural insult. Epileptogenesis is the process that occurs during this latent period, which transforms a relatively normal brain to one that is prone to chronic recurrent seizures. The mechanisms that underlie limbic epileptogenesis and subsequent emergence of seizures remain topics of intensive investigation, as does the elucidation of critical compensatory mechanisms that keep seizures under control. Numerous changes have been associated with epileptogenesis and subsequent seizure expression, including neuronal loss, increased excitation, altered inhibition, circuitry rearrangements, and individual synapse abnormalities. *

Fax: +1 301 295 3220. E-mail address: sbausch@usuhs.mil.

1525-5050/$ - see front matter. Published by Elsevier Inc. doi:10.1016/j.yebeh.2005.07.019

One dominant feature found in both humans and animal models is sprouting of hippocampal principal cell axons, which suggests that axonal sprouting may be a general phenomenon associated with temporal lobe epilepsy. This article examines some of these changes and reviews the findings suggesting that GABAergic interneurons also undergo axonal sprouting in temporal lobe epilepsy. The caveats and unanswered questions associated with the current data and the potential physiological consequences of reorganizations in GABAergic circuits are also discussed. Emphasis is placed on the hippocampus and dentate gyrus because the hippocampal formation is a common locus for seizures and alterations associated with acquired temporal lobe epilepsy. 2. Imbalance between excitation and inhibition? One popular hypothesis as to the cause of hyperexcitability coincident with epileptogenesis and emergence of seizures has been an imbalance between glutamate-mediated excitation and c-aminobutyric acid (GABA)-mediated inhibition [6–8]. This imbalance is thought to occur in part


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from axonal sprouting of excitatory principal cells and subsequent formation of recurrent excitatory networks together with a concurrent reduction in inhibition. 2.1. Excitation The hypothesis of an imbalance between excitation and inhibition predicts that an increase in recurrent excitatory synapses transforms normally ‘‘quiescent’’ neurons into an epileptogenic population, which facilitates seizure initiation and/or propagation of epileptiform activity [8]. Indeed, in the normal hippocampus, CA3 pyramidal cells have a high incidence of recurrent excitatory synapses and are the most prone of the hippocampal principal cells to epileptiform activity [9], while dentate granule cells and CA1 pyramidal cells exhibit negligible recurrent excitatory synapses and are more resistant to epileptiform events. Consistent with this hypothesis, many studies have documented an increase in functional recurrent excitatory circuitry in tissue isolated from humans and animal models with temporal lobe epilepsy. A type of synaptic reorganization termed mossy fiber sprouting is often associated with temporal lobe epilepsy in humans [10–12] and numerous animal models [13–17]. Mossy fiber sprouting is a pronounced expansion of a normally minor projection of the excitatory granule cell mossy fiber axons into the supragranular layers of the dentate gyrus [10–14,16,18–23] and within the hilus [24,25]. Anatomical and physiological studies have documented that sprouted mossy fiber collaterals synapse predominantly onto granule cells [25–28], suggesting that granule cells form synapses between themselves and thus create an aberrant recurrent excitatory network. Physiological studies have further shown that this aberrant excitatory network is functional and can dramatically increase granule cell excitability [14,29–33], which is suggestive of functional reactive synaptogenesis. CA1 pyramidal cells also have been documented to undergo axonal sprouting in the well-established kainic acid and pilocarpine models of temporal lobe epilepsy [34–37]. Physiological studies suggest that recurrent CA1– CA1 pyramidal cell circuits are also functional and can increase CA1 pyramidal cell excitability [34–44]. Despite unambiguous documentation of axonal sprouting in excitatory circuits, the precise role of this sprouting relative to seizure expression remains somewhat controversial. In support of a role for sprouting in excitatory pathways in limbic epilepsy, seizures have been documented in acute slices from kainic acid-treated epileptic rats with robust mossy fiber sprouting [30,31], and a positive correlation between mossy fiber sprouting and the frequency of spontaneous seizures has been reported in animal models in vivo [45,46]. Conversely, the degree of mossy fiber sprouting has not been a reliable indicator of the rate of epileptogenesis [46–48] or the severity, frequency, or number of seizures [48,49], and spontaneous limbic seizures can occur in the absence of mossy fiber sprouting [46,49–52].

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Nonetheless, the available data clearly indicate that increases in recurrent excitatory circuits contribute to the pathophysiological changes associated with temporal lobe epilepsy. Additionally, the association between temporal lobe epilepsy and sprouting of both mossy fibers and CA1 pyramidal cell axons suggests that axonal sprouting and functional reactive synaptogenesis may be a general phenomenon associated with limbic epileptogenesis. 2.2. Inhibition The hypothesis of an imbalance between excitation and inhibition also postulates that GABAergic inhibition is reduced in temporal lobe epilepsy. This idea arose partially because many antiseizure drugs increase GABAergic transmission, and agents that reduce GABAergic transmission can precipitate seizures. Furthermore, a partial loss of neurons that provide afferent input to GABAergic neurons [53,54], as well as a partial loss of GABAergic neurons themselves [10,53,55–58], is associated with temporal lobe epilepsy. Physiological studies in CA1 appear to substantiate the hypothesis. Persistent decreases in GABAergic inhibition have been reported in slices isolated from animal models of temporal lobe epilepsy [38–40,59–65]. However, a limited number of studies in CA1 also have revealed potential compensatory increases in GABAergic inhibition, including a partial recovery of diminished inhibition [39,59] and increased somatic inhibition despite reduced dendritic inhibition [66] at long times following kainic acid-induced seizures. The story is quite different in the dentate gyrus, however, where, although a transient depression of GABAergic inhibition occurs within 24 hours of the initial insult in a variety of animal models [17,67–69], GABAergic inhibition often recovers to normal, or even enhanced, levels at longer times in tissue isolated from both animal models and humans with temporal lobe epilepsy [29,65,69–82]. However, persistent reductions in inhibition also have been reported [63,68,83–87]. Thus, whether GABAergic transmission is increased, decreased, or unchanged remains a topic of debate. Numerous alterations in GABAergic systems have been proposed to compensate for the loss of GABAergic neurons and thereby restore or increase inhibition. In the dentate gyrus, in addition to forming recurrent granule cell synapses, supragranular mossy fibers also synapse onto GABAergic neurons [19,26], suggesting that GABAergic circuits are at least partially restored [17,29,53,75]. Altered postsynaptic GABAA receptor subunit composition [85,88–93] and GABAA receptor pharmacology [65,94], as well as increased levels of GABA [95,96] and postsynaptic GABAA receptors [81,97], also have been postulated to restore inhibition. However, given the possibility that axonal sprouting and functional reactive synaptogenesis may be a general phenomenon associated with temporal lobe epilepsy, axonal sprouting of GABAergic interneurons also may


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contribute to increased GABAergic transmission and, indeed, may require increased levels of GABA and GABAA receptors. 3. Axonal sprouting of GABAergic interneurons

Somatostatin (SS) Neuropeptide Y (NPY) Calbindin (CB)

Dendrite

3.1. Classification of interneurons GABAergic interneurons are defined by the expression and release of the neurotransmitter GABA. Accordingly, many studies suggesting axonal sprouting in GABAergic circuitry have used markers for GABA content including GABA, its synthesizing enzyme, glutamic acid decarboxylase (GAD), or the presynaptic neuronal GABA transporter, GAT-1. However, GABAergic interneurons in the hippocampal formation comprise diverse subpopulations [98–102] and are often further classified according to their axonal projections and termination zones, as well as their neuropeptide and calcium-binding protein expression [102]. Studies suggesting axonal sprouting of GABAergic neurons often have used a combination of these classifications. Although the debate on classification schemes for hippocampal GABAergic interneurons continues [103], in this article interneurons are divided into three broad groups based on published reports on axonal sprouting in GABAergic circuits: (1) dendritic interneurons, which synapse primarily onto dendritic regions; (2) perisomatic interneurons, including basket cells, which synapse onto somata and proximal dendrites, and axo-axonic cells, which innervate axon initial segments; and (3) interneuron-selective interneurons, which preferentially target other interneurons. Interneurons containing distinct neuropeptides and calcium binding proteins are placed into one of these groups for ease of discussion (Fig. 1). Caveats to these classifications are discussed in Section 3.6. Interneurons expressing the neuropeptides somatostatin (SS) and/or neuropeptide Y (NPY) or the calcium-binding protein calbindin (CB) are classified as dendritic interneurons because of their relative selectivity for dendritic innervation. SS interneurons primarily provide input to dendritic regions of entorhinal cortex innervation, namely, the outer two-thirds of the dentate molecular layer, with denser innervation to the outer third, and stratum lacunosum-moleculare of CA1. Occasional SS synapses also are found on hilar neurons, dentate granule cell somata, and in stratum oriens of CA1 [102]. The terminal fields of NPY interneurons exhibit partial overlap with SS, with dense innervation to the outer two-thirds of the dentate molecular layer and stratum lacunosum-moleculare of CA1. However, NPY interneurons also provide input to the stratum oriens and distal radiatum of CA1, as well as the granule cell layer and hilus, where postsynaptic targets are somata and dendrites of granule cells and presumed mossy cells [102]. CB interneurons primarily innervate principal cell dendrites [102] and, to a lesser degree, form perisomatic synapses [104]. CB axons provide a large input to stratum radiatum and lesser input to stratum oriens of

Soma

Parvalbumin (PV)

Cholecystokinin (CCK) Principal cell

Parvalbumin (PV)

Axon initial segment

Calretinin (CR) Calretinin (CR)

Fig. 1. Schematic of interneuron classification. For purposes of discussion, diverse subpopulations of GABAergic interneurons were classified according to their termination zones as well as their neuropeptide and calcium-binding protein expression. Interneurons expressing somatostatin, neuropeptide Y, and calbindin were classified as dendritic interneurons. Interneurons expressing parvalbumin and cholecystokinin were classified as perisomatic interneurons. Interneurons expressing calretinin were classified as interneuron-selective interneurons. Distinctions are based on relative selectivity and are not representative of all projections [102].

CA1. However, CB expression is not specific to interneurons, as dentate granule cells and the superficial layer of pyramidal cells in CA1 also express CB [102]. Interneurons expressing the calcium-binding protein parvalbumin (PV) or the neuropeptide cholecystokinin (CCK) are classified as perisomatic interneurons. PV interneurons comprise a subset of basket and axo-axonic cells in the hippocampus and dentate gyrus. PV terminal fields are dense and located almost exclusively in the principal cell layers and proximal stratum oriens, where their synapses surround proximal dendrites, somata, and axon initial segments of principal cells [102]. A second class of basket cells contains CCK. CCK terminal fields are located primarily in the principal cell layers and proximal dendritic regions, where their synapses surround proximal dendrites and somata of principal cells and occasionally somata of other interneurons [102]. Interneurons expressing the calcium-binding protein calretinin (CR) are classified as interneuron-selective interneurons. CR interneurons selectively innervate other interneurons in rodents, most notably other CR interneurons and non-PV-containing basket cells [105]. However, CR interneurons also innervate principal cell somata and dendrites in humans and nonhuman primates [106,107]. 3.2. Loss of interneurons Documentation of sprouting in GABAergic circuitry is complicated by the concurrent death of GABAergic interneurons, with some subpopulations exhibiting greater losses than others. In both humans and animal models of temporal lobe epilepsy, the greatest losses occur in GABAergic neurons expressing SS and, to a lesser degree, NPY


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[10,53,57,58,61,78,108–114]. Interneurons containing PV, CB, or CCK appear more resistant, although some loss does occur [53,61,78,104,108,109,115–119]. The relative vulnerability of CR interneurons is less clear, with different studies showing either particular vulnerability [116,117,120] or remarkable resistance [121,122]. However, despite the losses, many GABA- and GAD-positive interneurons survive in the hippocampus and dentate gyrus in both humans and animal models of temporal lobe epilepsy [55,110,113,123,124]. Evidence of axonal sprouting in the remaining interneurons must be interpreted in the context of the relative survival rate in each subpopulation. 3.3. Sprouting of dendritic interneurons A majority of reports suggesting axonal sprouting of GABAergic neurons have focused on the dendritic regions of dentate granule cells. Time course studies in the pilocarpine model revealed an early loss of GAD-immunoreactive (IR) fibers in the supragranular region and outer two-thirds of the dentate molecular layer [56] as well as GAT-1 [125] and GAD immunoreactivities [56] in the hilus. These data are consistent with the early partial loss of GABAergic interneurons in the pilocarpine model. However, although decreased GAT-1 immunoreactivity in the hilus persisted until the appearance of spontaneous recurrent seizures (10–18 days) [125], GAT-1 [125] and GABA [77] immunoreactivities were increased in the inner molecular layer by 6–9 days (the latent period) and persisted until periods of recurrent spontaneous seizures. Likewise, GAD immunoreactivity was increased in the inner molecular layer and, to a lesser degree, in the outer molecular layer at times P2 months following initial pilocarpine-induced status epilepticus [56]. Studies performed at longer single time points following the initial insult also suggest axonal sprouting of GABAergic interneurons into granule cell dendritic regions. Increased GAD or GAT-1 immunoreactivity has been documented in the inner molecular layer in the kainic acid [126], electrical stimulation-induced status epilepticus [127], and pilocarpine [125] models and in the outer molecular layer in the pilocarpine [56] and electrical stimulationinduced status epilepticus [127] models. Consistent with data obtained in animal models, increases in GAD immunoreactivity in the inner molecular layer [113,128] and GAT-1 immunoreactivity throughout the molecular layer [128] have been documented in human epileptic hippocampus. Taken together, these data suggest an early loss of innervation followed by sprouting in GABAergic circuitry in the dendritic regions of dentate granule cells. The data further suggest that sprouting in GABAergic circuitry is an early event that precedes the appearance of spontaneous recurrent seizures. Results from studies using SS and NPY as selective markers for dendritic interneurons are in partial agreement with studies using general markers for GABAergic neurons. In human epileptic tissue, SS-IR fibers were increased throughout the molecular layer [110,111,113]. Electron

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microscopy also revealed SS-IR terminals throughout the molecular layer and some SS-IR terminals forming symmetric (inhibitory) synapses within the inner molecular layer [110]. Likewise, in animal models SS-IR fibers were increased in the outer molecular layer in the pilocarpine [87], kainic acid [78], kindling [129], rapid kindling, and electrical stimulation-induced status epilepticus [114] models, and in the middle third of the molecular layer in the rapid kindling and electrical stimulation-induced status epilepticus [114] models. Consistent with the partial overlap of SS with NPY in GABAergic interneurons, increases in NPY-IR fibers in the human epileptic hippocampus were observed throughout the dentate molecular layer [10,110,111,113]. However, increases in NPY-IR fibers were most profound in the inner molecular layer [10,110]. Similarly, in animal models, increases in NPY-IR fibers were observed throughout the dentate molecular layer following electrical stimulation-induced status epilepticus [114] and in the outer and middle thirds of the dentate molecular layer following rapid kindling [114]. Increases in NPY-IR fibers were greatest in the inner molecular layer following electrical stimulation-induced status epilepticus in rats [114]. Under normal conditions, NPY terminal fields are rare in the inner molecular layer [102]. Early studies in the pilocarpine model initially suggested that rearrangements in GABAergic circuitry also may occur in the hippocampal CA1 region because GAD immunoreactivity was increased in stratum radiatum [56] and stratum lacunosum-moleculare [56,130]. However, in the same model, persistent decreases of GAT-1-IR fibers in strata oriens and radiatum [125], no change in symmetric synapse number in stratum radiatum, and a 40% decrease in symmetric synapses in stratum lacunosum-moleculare [66] suggested that sprouting of GABAergic interneuron axons to principal cell dendritic regions does not occur in CA1. This said, rearrangements in dendritic interneuron circuitry have been reported in hippocampus isolated from humans with temporal lobe epilepsy, albeit onto other GABAergic neurons. CB dendritic interneurons in CA1 received a 3.5-fold greater percentage of symmetric dendritic synapses in epileptic tissue and shifted their postsynaptic target selectivity from primarily pyramidal cells and CB-negative dendrites (90%) in controls to an equal probability for pyramidal cells/CB-negative neurons and other CB-IR interneurons in epileptic tissue. Changes were observed in strata oriens, pyramidale, radiatum, and lacunosum-moleculare [104]. Thus, increases in GAD immunoreactivity in strata radiatum and lacunosummoleculare in the pilocarpine model may reflect sprouting of GABAergic interneurons onto other interneurons. To summarize, a great deal of evidence suggests sprouting of dendritic GABAergic interneurons in both the dentate gyrus and CA1 region in the epileptic hippocampus. Sprouted GABA-, GAD-, GAT-1-, SS-, and NPY-IR axons in the dentate gyrus seem to innervate dendritic regions of excitatory granule cells, although the precise


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postsynaptic targets have yet to be reported. In contrast, sprouted CB-IR and possibly GAD-IR axons in CA1 appear to preferentially innervate dendrites of other inhibitory interneurons. 3.4. Sprouting of perisomatic interneurons Slight increases in GAD-IR terminals in hippocampal pyramidal cell layers in the pilocarpine model [56] and increases in GAT-1-IR fibers in the granule cell layer of the seizure-sensitive gerbil [131,132] raised the possibility that perisomatic innervation of principal cells also is increased in both the dentate gyrus and CA1 in temporal lobe epilepsy. Indeed, in human epileptic tissue, light microscopy studies have shown that PV-IR basket formations surrounding granule cells and PV-, GAT-1-, and CB-IR boutons covering putative granule cell axon initial segments were increased [133]. Although ultrastructural analysis showed no change in the number of symmetric synapses onto granule cell somata, a threefold increase in symmetric synapses onto axon initial segments of granule cells [118] was observed in epileptic tissue compared with controls. Moreover, in animal models, CCK-IR fibers from putative perisomatic basket cells were increased in the inner dentate molecular layer in the kainic acid [134] and rapid kindling [114] models and the middle molecular layer following electrical stimulation-induced status epilepticus [114], suggesting sprouting of CCK axons. However, whether alterations in CCK circuitry represent increased basket formation onto other GABAergic interneurons, or an expansion of CCK innervation to more distal granule cell dendrites, remains to be addressed. Light microscopy studies in the CA1 region of the human epileptic hippocampus also have revealed dramatic increases in the number of PV-, GAT-1-, and CB-IR boutons surrounding putative axon initial segments and more dense PV-IR basket formations surrounding surviving CA1 pyramidal cells [133]. However, unlike similar studies in the dentate gyrus, electron microscopy analyses revealed no change in the number of symmetric synapses onto CA1 pyramidal cell somata or axon initial segments [119]. In animal models, increases in CCK-IR fibers from putative perisomatic basket cells were observed in all pyramidal cell layers in the kainic acid [134], rapid kindling, and electrical stimulation-induced status epilepticus [114] models, suggesting increased perisomatic innervation. However, as in humans, electron microscopy revealed no change in the number of symmetric synapses onto CA1 pyramidal cell somata in the pilocarpine [135] and kainic acid [136] models and no change in the number of symmetric synapses onto CA1 pyramidal cell axon initial segments in the kainic acid model [137]. In fact, decreases in symmetric synapses onto axon initial segments of CA1 pyramidal cells also have been described in the pilocarpine model [138]. Despite the apparent maintenance of perisomatic innervation to pyramidal cells in humans and animal models with temporal lobe epilepsy, increases in perisomatic

synapses have been reported in the CA1 region in animal models. As with dendritic interneurons in CA1, these synapses appear to target other interneurons. Significant increases in perisomatic GABAergic synapses onto other interneurons have been noted in stratum lacunosum-moleculare using electron microscopy in the kainic acid model [136]. Consistent with this finding, CCK-IR fibers were increased in stratum lacunosum-moleculare in the rapid kindling, electrical stimulation-induced status epilepticus [114], and kainic acid [134] models. However, whether increased CCK-IR fibers reflect increased perisomatic synapses onto interneurons or an expansion of CCK innervation to more distal CA1 pyramidal cell dendrites remains to be determined. In summary, current data suggest that, similar to dendritic interneurons, sprouting of perisomatic GABAergic interneurons occurs in both the dentate gyrus and CA1 in the epileptic hippocampus. Strong electron microscopic evidence suggests that sprouted axons in the dentate gyrus target perisomatic regions of the excitatory granule cells, while sprouted axons in CA1 preferentially innervate somata of other inhibitory GABAergic neurons. 3.5. Sprouting of interneuron-selective interneurons Documentation of a dramatic expansion of CR-IR fibers in the dentate molecular layer of human epileptic tissue suggests that sprouting of interneuron-selective interneurons also is associated with temporal lobe epilepsy. Whereas CR-IR fibers were restricted to the inner molecular layer in controls, CR-IR was observed throughout the entire width of stratum moleculare in epileptic tissue [117,121]. Although a proportion of the synapses were asymmetric, which is a feature of CR innervation arising from the supramammillary nucleus in primates [117,121], there was a fourfold increase in the frequency of symmetric CR-IR synapses throughout the molecular layer, which is indicative of terminals from dentate gyrus interneurons [117]. Symmetric synapses contacted unlabeled dendrites and somata and other CR-IR dendrites [121]. However, the proportional increases in synapses onto excitatory granule cells and inhibitory interneurons remain unclear, as CR interneurons also innervate principal cells in primates. 3.6. Caveats and questions Extensive evidence from humans and animal models is consistent with the idea that, like the excitatory principal cells, inhibitory GABAergic interneurons undergo axonal sprouting in temporal lobe epilepsy. However, several important caveats temper the interpretation of the available data. The first and most prominent pertains to the use of indirect markers, such as GABA, GAD, GAT-1, neuropeptides, and calcium-binding proteins, to document axonal sprouting. Interpretation of data obtained using indirect markers can be confounded by alterations in expression levels. Indeed, increased expression of GABA


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[96], GAD [130,139,140], somatostatin [78,87,112,114, 129,141], NPY [112,114,142], and CCK [114,134,143] has been observed in surviving interneurons in animals models of temporal lobe epilepsy. Such increases can enhance detectability and give the impression of increased numbers of fibers and terminals. Shrinkage of analyzed regions also can increase fiber density without altering profile number. Furthermore, markers specific to GABAergic neurons in control hippocampus may not show the same specificity in epileptic tissue. For example, hyperactivity and seizures can transiently upregulate the expression of GABA and GAD in dentate granule cells [144–147] and markedly induce the expression of NPY in granule cells and their terminal fields, including a persistent band in the inner molecular layer [112,114,148]. Therefore, data showing increases in GABA, GAD, and NPY immunoreactivities in the inner dentate molecular layer may reflect sprouted mossy fibers, rather than axons of GABAergic interneurons. Similarly, markers specific to defined subpopulations of interneurons in controls may be induced in other populations of interneurons in epileptic tissue. This said, the profound early loss of GABAergic interneurons followed by the later dramatic increases in immunoreactive fibers, especially in SS and NPY interneurons, suggest that increased expression of markers alone cannot account fully for the observed alterations. Electron microscopic evidence documenting increases in symmetric synapses onto dendrites of CA1 CB interneurons, somata of stratum lacunosum-moleculare interneurons, and axon initial segments of dentate granule cells provides the most compelling argument for rearrangements in GABAergic axons to date. However, it remains unclear whether increased synapses require sprouting of new axon collaterals or arise from new terminals on existing axons. Moreover, the identity of the subpopulation(s) of interneurons providing increased synapses is unclear, as sprouting may cause a shift in the dominant synaptic fields of hippocampal interneurons. Indeed, seizure-induced sprouting in excitatory circuits causes dramatic expansions in normally minor projections (see Section 2.1), and CB-IR dendritic interneurons have been shown to shift their postsynaptic target preferences in epileptic tissue (see Section 3.3). Another unanswered question is whether the apparent maintenance of synapses onto CA1 pyramidal cell and dentate granule cell somata reflects maintenance per se. Findings of no change in the number of perisomatic synapses also could result from an early decrease in synapses due to the partial loss of GABAergic interneurons followed by a restoration of synapses from compensatory sprouting. Time course studies in animal models are needed to resolve this matter. 4. Functional consequences of axonal sprouting of GABAergic interneurons On a simplistic level, findings suggesting that GABAergic axons form new synapses onto excitatory granule

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cells imply increased inhibition and thus support the physiological data describing enhanced inhibition in the dentate gyrus of epileptic tissue. Moreover, increased numbers of GABAergic synapses onto other inhibitory interneurons in CA1 suggests disinhibition, which supports the physiological findings of reduced inhibition in the epileptic CA1. However, this simplified interpretation relies on three major assumptions: (1) that all GABAergic synapses perform the same function; (2) that GABAergic transmission is always inhibitory; and (3) that GABAergic synapses are equivalent in the normal and epileptic states. Flaws are evident in each of these assumptions and impact the functional consequences of axonal sprouting in GABAergic interneurons in the epileptic hippocampus. 4.1. Sprouting, location and function—not created equal GABAergic synapses often do perform the same basic function, i.e., elicit GABA receptor-mediated inhibition. However, the subcellular targeting of GABAergic synapses is paramount to their effect on network function. Dendrites are responsible primarily for synaptic integration and signal processing. Thus, dendritic GABAergic synapses are poised to shape the input to individual neurons. However, terminal fields of dendritic interneurons are normally sparse and limited in distribution. Therefore, activation of dendritic interneurons rarely generates the simultaneous inhibitory postsynaptic potentials (IPSPs) required for efficient inhibition in postsynaptic dendrites [149]. Increased GABAergic synapses from sprouted dendritic interneurons onto individual principal cells could increase simultaneous IPSPs and provide more efficient dendritic GABAergic inhibition. CR interneuron-selective interneuron sprouting onto other CR and dendritic interneurons (see Section 3.5) also could increase the incidence of simultaneous IPSPs, because CR interneurons are thought to be electrically coupled via gap junction-like specializations and participate in dendritic interneuron synchronization [102,150]. In contrast to dendrites, axons are responsible for action potential initiation and propagation. Therefore, perisomatic interneurons, particularly the axo-axonic cells, are positioned to limit action potential firing and control neuronal output [149]. As axo-axonic cells synapse exclusively on excitatory principal cell axon initial segments [151,152], sprouting of axo-axonic cells could reduce principal cell firing and thereby limit the generation and/or propagation of seizures. However, perisomatic interneurons also play a pivotal role in oscillatory and synchronous activity [102,152–154], which is thought to be due to dense and far-reaching terminal fields, extensive gap junction-mediated electrical coupling, and recurrent synaptic innervation, especially between basket cells [149,153,154]. Thus, increased perisomatic innervation also might enhance the synchronous activity associated with seizures.


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4.2. Sprouting and GABAergic transmission—not always inhibitory GABAA receptor-mediated responses are often strongly inhibitory in the healthy adult. Responses consist of robust shunting of excitatory currents [155] and a large increase in membrane conductance, mediated primarily by Cl influx and, to a lesser degree, by HCO3 efflux [156,157]. Although the net result is often membrane hyperpolarization, the consequences of GABAA receptor activation on membrane potential are strongly dependent on the resting membrane potential and the Cl gradient across the membrane. During prolonged GABAA receptor activation, an initial hyperpolarizing response is seen, but over time the profound Cl influx overpowers the ability of K+–Cl cotransporter to export excess Cl . This causes Cl to build up inside the cell, which eliminates the Cl gradient and allows the HCO3 efflux to predominate. The net result is a depolarizing GABAA receptor-mediated response. Such a depolarizing GABA response has been observed following prolonged activation of GABAA receptors in principal cell dendrites but not somata [158,159]. Therefore, the physiological consequences of sprouting in dendritic interneurons are not clear-cut. An increase in GABAergic synapses onto excitatory principal cell dendrites may increase inhibition and dampen the effects of excess excitatory inputs under basal physiological conditions, but also could enhance excitation during the prolonged activity associated with seizures. 4.3. Sprouting and equivalence—not in temporal lobe epilepsy The assumption that GABAergic synapses are equivalent in the normal and epileptic states is almost certainly false. Despite recovery or increased synaptic contacts in some GABAergic circuits, deficits are likely to remain in others (i.e., dendritic innervation to CA1 pyramidal cells). Moreover, functional alterations in surviving interneurons and at individual GABAergic synapses have been reported in the epileptic hippocampus. In slices from epileptic rats, increased firing frequency and spontaneous excitatory input have been documented in CA1 interneurons, yet spontaneous inhibitory activity in CA1 pyramidal cells was increased in somata but decreased in dendrites in epileptic tissue [66]. Also, despite the apparent maintenance of perisomatic symmetric synapses onto CA1 pyramidal cells, these synapses exhibited a 50% decrease in the reserve vesicle pool and in the probability of quantal GABA release in epileptic compared with control tissue [135]. General alterations in GABAergic function also have been reported, including changes in G-protein-coupled receptor modulation of GABAergic transmission [68,76,77,160], zinc-induced collapse of augmented GABAergic inhibition [84], and, as already stated (see Section 2.2), altered postsynaptic GABAA receptor subunit composition and GABAA receptor pharmacology, as well as increased levels of

GABA and postsynaptic GABAA receptors. Moreover, neuropeptides are not merely markers for subpopulations of GABAergic interneurons, but play important roles in regulating brain excitability. Neuropeptides like SS, NPY, and CCK are generally inhibitory and often antiepileptic [102,161,162]. The dramatic seizure-induced loss of neurons expressing these inhibitory neuropeptides (see Section 3.2) is likely to impact network function, despite up regulation of SS, NPY, and CCK expression (see Section 3.6) in surviving interneurons. These examples represent just a few of the many alterations in GABAergic function that have been documented in temporal lobe epilepsy. Thus, even if axonal sprouting could completely restore all synapses lost due to the partial loss of GABAergic interneurons in the epileptic hippocampus, these synapses are unlikely to function normally. 5. Conclusions Despite the unanswered questions and limitations of the current data, great strides have been made in the documentation of axonal rearrangements in GABAergic interneurons. It now appears quite likely that synaptic reorganization in both excitatory and inhibitory circuits is a general phenomenon associated with temporal lobe epilepsy. The extent of GABAergic interneuron sprouting, as well as the identity of the presynaptic neurons and postsynaptic targets, awaits definitive documentation, and may be region-specific (i.e., different between the dentate gyrus and CA1). However, the functional consequences of rearrangements in GABAergic circuitry are unresolved, especially within the framework of network function, different activation states, and other changes in GABAergic circuitry associated with temporal lobe epilepsy. While axonal sprouting in GABAergic circuits is often thought of as a compensatory mechanism to balance increased excitation, emerging evidence suggests that it also may play a contributory role in the emergence of seizures. Acknowledgments I thank Dr. Carrie T. Drake and Dr. Lori L. McMahon for discussions and critical reading of this article. Work was supported by National Institute of Neurological Disorders and Stroke Grant NS042346. The opinions or assertions contained herein are the private ones of the author and are not to be construed as official or reflecting the views of the Department of Defense or Uniformed Services University. References [1] Hauser WA, Kurland L. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1937. Epilepsia 1975;16:1–66. [2] Cahan L, Sutherling WW, McCullough M, Rausch R, Engel J, Crandal PH. Review of the 20 year UCLA experience with surgery for epilepsy. Cleve Clin Q 1984;51:313–8.


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Axonal Sprouting of GABA in TLE