1.1. Diversity of Cortical GABAergic Interneurons Subtypes and Roles

Neocortical GABAergic INs are heterogeneous, and different subtypes of INs have different spatial and temporal origins. As a group, neocortical INs are derived from transient ventral telencephalic structures referred to as the ganglionic eminences [27, 29, 41–46] as well as from the preoptic area [47]. The medial ganglionic eminence (MGE) produces approximately 70% of neocortical INs, including the parvalbumin-positive (PV) fast-spiking interneurons and the somatostatin-positive (SST) interneurons, which represent 40% and 30% of all neocortical INs, respectively [27, 46, 48]. By contrast, the caudal ganglionic eminence (CGE) gives rise to the remaining 30% of neocortical INs, a more heterogeneous group of cortical INs that share the unique expression of 5HT3A ionotropic serotoninergic receptors, rendering them highly responsive to the neuromodulatory effects of serotonin [9, 43, 46, 48, 49]. A majority of CGE-derived interneurons belong to either the reelin-positive multipolar population (including the late-spiking neurogliaform cells), the vasointestinal-peptide- (VIP-) positive bitufted population (including a calretinin- (CR)-positive population), or the VIP-positive, calretinin-negative bipolar population. Finally, the preoptic area contributes a small portion of neocortical INs (<3%) that are not labelled by the usual interneuron markers mentioned above [47]. The lateral ganglionic eminence (LGE) mainly produces olfactory bulb and amygdalar INs, as well as striatal and nucleus accumbens medium spiny neurons, but is generally thought not to give rise to cortical INs [23, 33, 38, 41, 50, 51]. Different subtypes of cortical INs are identified based on their immunohistochemical, morphological, physiological, and connectivity properties, and they mediate different functions in mature networks as detailed below.

1.2. Parvalbumin-Positive Basket Cells

PV-positive interneurons include the perisomatically targeting basket cells and the less abundant axon-initial segment-targeting chandelier cells. PV-positive basket cells can be further divided according to various morphological characteristics, including somatic diameter, firing properties, and extent of dendritic and axonal arborisation [5, 9, 52, 53]. As a group, PV-positive basket cells display many characteristics which render them one of the fastest and most reliable sources of inhibition in the cortex. They exhibit low input resistance, fast membrane kinetics, brief action potentials with large afterhyperpolarisation, and minimal spike adaptation and are able to sustain high frequency firing rates [5, 18, 19, 21, 44, 52, 54]. These fast kinetics are partly due to their expression of Kv3 voltage-gated potassium channels [52, 55–59], which ensure quick repolarisation and termination of action potentials. In addition, PV-positive fast-spiking cells mediate fast reliable neurotransmission, as they rely mainly on P/Q-type presynaptic Ca²⁺ channels for tight coupling between action potentials and neurotransmitter release [60–63]. Furthermore, these PV-positive basket cells might be able to buffer calcium more efficiently, as they express high levels of Ca²⁺-binding proteins, including parvalbumin and calbindin. It is possible that this expression of Ca²⁺-binding proteins renders these cells more resistant to Ca²⁺-induced excitotoxicity in the face of high firing rates.

PV-positive INs are the main inhibitory target of thalamocortical projections in the cortex. In addition, PV-positive basket cells form intricate nests of synaptic contacts on the soma of adjacent pyramidal cells, giving them rapid control over the excitability of their pyramidal cell targets. These INs are therefore well positioned to provide strong and fast feedforward inhibition to adjacent pyramidal cells, limiting the time window for temporal summation of excitatory inputs and spike generation within populations of pyramidal cells. This feature sharpens the cortical response and prevents runaway excitation following thalamocortical excitation [64–68].

In addition, PV-positive basket cells are highly interconnected with one another through both chemical and electric synapses (gap junctions), creating a vast web of synchronously active INs [69, 70]. This network of inhibitory INs triggers and maintains high-frequency gamma oscillations within ensembles of cortical pyramidal cells [69, 71–77]. In support of this, the loss of connexin32, which forms gap junction connections between PV-positive INs, results in the partial loss of task-induced gamma oscillations [78]. Gamma oscillations are important for the maintenance of attention, working memory, and the refinement of executive functions in humans and rodents [79–83]. Therefore, PV-positive interneuron dysfunction has been postulated to underlie the loss of gamma oscillations in schizophrenic patients displaying working memory and executive function abnormalities [14, 82, 84, 85].

1.3. Parvalbumin-Positive Chandelier Cells

Like PV-positive basket cells, PV-positive chandelier cells display brief nonadapting trains of action potentials upon stimulation and are able to sustain high frequency firing rates [17, 86, 87]. They are characterised morphologically by their cartridges of vertically oriented candlestick-like axonal arbors [88–90]) forming synapses on the axon initial segment (AIS) of pyramidal cells [89, 91]. Chandelier cells are unusual among interneurons in that their output has been postulated to be excitatory rather than inhibitory. Indeed, the stimulation of chandelier cells triggers depolarisations in target pyramidal cells in the cortex and dentate gyrus [92–95]. This has been attributed to the high concentration of chloride and elevated GABA_A reversal potential at the AIS, due to efficient Cl⁻ import by the NKCC1 transporter in the absence of the KCC2 transporter (see below) [92, 93]. However, it is still unclear whether such depolarizing responses are obligatorily excitatory [95]. Furthermore, in other circuits, such as in the CA1 region of the hippocampus, chandelier cells appear to trigger hyperpolarising responses [96]. Overall, the net effect of chandelier cells might be dependent on the local state of network activity and on the particular ion channel composition of local pyramidal cells in different brain regions. In vivo, chandelier cells might be involved in the generation of specific oscillatory activities as they fire immediately before hippocampal pyramidal cells during sharp-wave-associated ripples [97].

1.4. Somatostatin-Positive (SST) Interneurons

Somatostatin-positive interneurons, including Martinotti cells and non-Martinotti cells, are heterogeneous in terms of their immunohistochemical profile (variable colabelling with calretinin and calbindin), morphology (multipolar, bipolar, or unipolar), axonal projections (most target pyramidal cell dendrites in layer I but some project locally within their cortical layer), and intrinsic electrophysiological properties [9, 45, 98–100]. A majority of SST interneurons (including the Martinotti cells) share some physiological characteristics, including a low spike threshold, prominent after-hyperpolarisation, and spike rate adaptation. However, these cells differ in their spiking pattern at threshold (regular versus bursting), especially when fired from hyperpolarized step currents [17, 98, 99]. In general, compared to fast-spiking basket cells, SST-positive interneurons tend to be more excitable: they display a lower spike threshold and have a higher resting membrane potential [101]. One exception to this rule is a population of non-Martinotti cells, which have a high firing threshold, higher firing rate, shorter spike half width, and lower input resistance [45, 99]. These cells have been mostly described in layer 4 of the cortex and are preferentially labelled in the X94 GAD67-GFP transgenic line [9, 99].

SST-positive Martinotti cells are found across cortical layers II-VI but are most abundant in cortical layer V. They project vertically towards layer I where they contact pyramidal cell dendrites and extend multiple axonal collaterals towards adjacent cortical columns [19, 102, 103]. Martinotti cells regulate pyramidal cell excitability by controlling the dendritic summation and integration of synaptic inputs and sharpening the coding of stimulus intensity [104]. Furthermore, as their connectivity is simultaneously divergent, convergent, and recurrent, they mediate disynaptic inhibition between interconnected pyramidal cells as well as recurrent feedback inhibition onto presynaptic pyramidal cells [105, 106]. They are therefore well suited to prevent excessive and recurrent excitation within cortical networks. Furthermore, they are increasingly recruited by sustained stimulation, owing to the fact that the synapses that they receive from pyramidal cells are in most cases facilitating [101, 107]. This renders them good candidates to dampen excitation during high activation states. Dysfunction of somatostatin cells has therefore been postulated to underlie some forms of experimental or poststatus epilepticus seizure disorders [108].

Because of their expression of low-threshold voltage-gated calcium channels and persistent sodium currents, about 40% of SST cells display intrinsic bursting abilities and might act as pacemaker cells, thereby triggering particular cortical oscillations [224]. Indeed, SST-positive cells, which are highly interconnected via gap junctions, tend to oscillate spontaneously in the theta range (3–9Hz) when stimulated electrically or with cholinergic agonists in vitro [101]. They could therefore be involved in pacing cortical pyramidal cells in the theta range.

1.5. Vasoactive Intestinal Peptide- (VIP-) Positive Interneurons

CGE-derived interneurons tend to populate more superficial cortical layers than MGE-derived interneurons. Approximately 40% of CGE INs express VIP, and these cells tend to be enriched in layers II/III [19, 46, 48, 225, 226]. VIP-positive INs are diverse morphologically, histochemically, and physiologically [9]. The most abundant type are the bitufted VIP+ INs that tend to colabel with CR [46, 48], display an irregular-spiking firing pattern near threshold [18, 46, 48, 49, 227], and send a downward projecting axon towards deeper cortical layers. The second most abundant type is the VIP+, CR− bipolar cells, which display a fast adapting firing pattern [44, 46, 48, 227] and send extensively branched projections both locally and towards deep cortical layers. Due to their high input resistance, VIP INs tend to be highly excitable [18, 46, 48]. They have been shown to target pyramidal cell dendrites and somata [17], but some subsets appear to target other interneurons more preferentially [228–230]. The precise function of VIP interneurons in cortical networks remains to be determined. However, their physiological characteristics and diverse synaptic targets render them well suited to rapidly modulate the interactions between pyramidal cells and MGE-derived interneurons. Furthermore, as they receive strong input from pyramidal cells in layers II-III [231], which also receive input from pyramidal cells in other functionally connected cortical areas, VIP interneurons might be important in regulating cross-cortical communication (i.e., sensorimotor modulation where inputs from the sensory cortex modulate the output of cortical motoneurons).

5.1. Interneuron Development in Humans

Human GABAergic interneurons appear to be highly diverse as initially recognized by Ramon y Cajal [283, 284], with a similar array of PV-positive basket cells, PV-positive chandelier cells, SST-positive Martinotti cells, VIP-CR bitufted cells, VIP bipolar cells, and neurogliaform cells as that described in other species [284, 285]. However, the relative proportion of these various populations varies across species [286]. The superficial cortical layers II-III are considerably larger in the human cortex, presumably underlying some of the enhanced intercortical connectivity mediating higher brain functions in primates. Consequently, CR-positive double-bouquet INs appear to be considerably more numerous in the human cortex [284, 285]. Furthermore, although most cortical GABAergic interneurons develop in the ventral ganglionic eminences in humans, a proportion of cortical INs appear to originate from the cortical ventricular zone [284, 287–289]. Nonetheless, similarities do exist with regards to the molecular pathways involved in cortical interneuron genesis in humans and rodents, with preservation of some of the same fundamental genes including Mash1, Dlx1/2, Nkx2-1, and Lhx6 [288, 290–293].

5.2. Interneurons and Schizophrenia

Schizophrenia is a chronic psychiatric condition that combines neurocognitive dysfunctions (i.e., delusions, hallucinations, and disorganisation of thought), negative symptoms (i.e., flat affect, avolition, and alogia), and social or occupational deterioration (i.e., altered social interactions, deterioration in personal hygiene, and inability to self-sustain) [294]. This is accompanied by more specific cognitive impairments such as abnormalities in perception, inferential thinking, volition, linguistic fluency, attention, executive functions (planning), and working memory [295, 296].

The involvement of interneurons in the pathophysiology of schizophrenia was suggested when the number of prefrontal cortical GAD67-expressing cells was found to be decreased in autopsy specimens from schizophrenic patients [109, 110]. There is no net loss of cortical PV-positive interneurons or calretinin-positive interneurons in schizophrenic cortices, as the total number of cells stained for either marker is preserved [111, 112]. However, there appears to be a selective downregulation of GAD67 in PV-positive interneurons in schizophrenic brains [112]. Furthermore, the level of parvalbumin expression in these cells is decreased [112]. As both parvalbumin and GAD67 expression are known to be regulated by cortical activity [297, 298], these findings could reflect secondary changes in response to altered levels of cortical activity in schizophrenic patients. Indeed, two schizophrenia susceptibility genes encoding the trophic factor neuregulin 1 (NRG1) and its receptor ErbB4 (ERB4) [117–121] have been shown to facilitate activity-dependent GABA release from PV-positive basket cells in the mouse prefrontal cortex [299]. Selective loss of ErbB4 in PV cells causes a disinhibition of prefrontal pyramidal cells and results in a schizophrenia-like phenotype in mice [126]. In addition, the specific expression of ErbB4 in PV cells is required for neuregulin-1-dependent regulation of hippocampal long-term potentiation [127], which is altered in schizophrenic patients. Interestingly, hypostimulation of PV-positive basket cells via selective ablation of the NR1 subunit of the NMDA receptors in these cells resulted in schizophrenia-like behaviors (working memory deficits, impaired prepulse inhibition, locomotor hyperactivity, and anxiety) and decreased PV and GAD67 expression in PV basket cells in a mouse model of schizophrenia [128]. Therefore, hypofunction of prefrontal PV INs, either through a primary dysfunction of these cells or a decreased excitatory drive to these cells, appears to result in behavioural consequences in mice, which recapitulate aspects of the phenotype observed in schizophrenic patients.

Additionally, other genetic anomalies found in schizophrenic patients that are predicted to affect cortical maturation more broadly appear to impact interneuron maturation and GAD67 expression. For instance, brain-derived neurotrophic factor (BDNF) is normally released in an activity-dependent fashion from pyramidal cells and was shown to regulate the maturation of GABAergic INs [129]. Both BDNF and its receptor TrkB have been found to be downregulated in the prefrontal cortex of schizophrenic patients [122–124]. Knock-out mice for both BDNF and TrkB display behavioral anomalies and a decrease in the synaptic expression of GAD67/GABA [130, 131]. Similarly, the neural cell adhesion molecule NCAM, important for neuronal morphological maturation and synapse formation, requires the addition of a polysialic acid (PSA) moiety to function properly. The activity-mediated expression of PSA has been shown to regulate PV-positive basket cell maturation and determine critical-period plasticity [132]. Interestingly, this PSA-NCAM coupling has been reported to be decreased in hippocampal specimens from schizophrenic patients [125], which would suggest abnormalities in interneuron maturation and cortical plasticity.

Another interesting hypothesis is that PV-positive chandelier cells might be affected in schizophrenic brains. Indeed, a specific loss of more than 40% of the axonal cartridges (the GAT-1 positive axonal branches from chandelier cells which contact the axon initial segments of pyramidal cells) has been demonstrated in the prefrontal cortex of schizophrenic patients [114, 115]. This is accompanied by enhanced expression of the alpha2 GABA_A receptor subunit on the axon initial segment of pyramidal cells, likely as a compensatory mechanism for the decreased input from chandelier cells [300]. However, since chandelier cells are possibly excitatory [94, 95], the net effect of these structural changes on local cortical excitability is uncertain. More recently, the levels of SST, NPY, and CCK were shown to be decreased in a microarray analysis of prefrontal cortical samples from schizophrenic patients [116] (Table 1). Furthermore, there seems to be a specific decrease in SST-positive interneurons, as shown by in situ hybridisation staining, in these samples [116]. However, these results await replication.

Table 1

Findings in schizophrenic patients and correlations in mice models.

Findings		References
Humans
GAD67	↓ GAD67 in prefrontal cortex	Volk et al. [109]
		Akbarian et al. [110]
	Preserved # number of PV cells, cortex	Woo et al. [111]
		Hashimoto et al. [112]
	↓ GAD67 level in PV cells, cortex	Hashimoto et al. [112]
	Association with polymorphisms in GAD67 promoter	Addington et al. [113]
Chandelier	Decrease in chandelier cells cartridges (GAT1+) in prefrontal cortex	Woo et al. [114]
		Volk et al. [115]
SST	↓ levels of SST in microarray analysis and ↓number of SST cells, prefrontal cortex	Hashimoto et al. [116]
NPY/CCK	↓ levels of NPY and CCK in microarray analysis	Hashimoto et al. [116]
NRG1	Susceptibility locus in NRG1	Stefansson et al. [117, 118]
		Zhang et al. [119]
		Yang et al. [120]
ERB4	Susceptibility locus in ERB4	Silberberg et al. [121]
BDNF/Trkb	Downregulation of BDNF in prefrontal cortex	Weickert et al. [122]
		Wong et al. [123]
	Downregulation of BDNF and Trkb in prefrontal cortex	Takahashi et al. [124]
PSA/NCAM	↓ PSA-NCAM complexes in hippocampus	Barbeau et al. [125]
Gamma	Gamma oscillations are triggered by working memory tasks + selective attention	Tallon-Baudry et al. [79]
		Howard et al. [81]
	Decreased power of cortical gamma oscillations and phase locking to memory task	Spencer et al. [82, 84]
		Cho et al. [85]
Mice
Erb4	Selective interneuron loss of Erb4: “schizophrenia-like behaviors”	Wen et al. [126]
Erb4/Nrg1	Erb4 in PV cells is required for Nrg1-dependant regulation of LTP (hippocampus)	Chen et al. [127]
NR1	Selective loss of the NMDAr NR1 subunit in PV cells: decreased excitatory input to PV cells results in “schizophrenia-like behaviors” and ↓ expression of PV and GAD67	Belforte et al. [128]
BDNF	BDNF regulates activity-dependant maturation of PV cells Bdnf−/− and Trkb−/−: ↓ synaptic GAD67 and GABA and behavioral anomalies	Huang et al. [129]
		Cotrufo et al. [130]
		Hashimoto et al. [131]
PSA/NCAM	Activity-mediated expression of PSA regulates PV cells maturation and visual plasticity	Di Cristo et al. [132]
Gamma	Gamma oscillations are triggered by stimulating PV cells: enhanced performance	Cardin et al. [77]
		Sohal et al. [83]
	Gamma oscillations depend on PV cells-mediated fast-synaptic inhibition	Bartos et al. [72]

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Nonetheless, even if the numbers of various interneuron subtypes are preserved and if the morphological structure of these cells is intact in most cases, functional abnormalities in the connectivity of GABAergic circuits likely play a role in the pathogenesis of psychiatric disorders. Modifications of the specific GABA_A receptor subunits expressed in the prefrontal cortex of schizophrenic patients have been described [116, 301]. Furthermore, cortical prefrontal gamma oscillations triggered by working memory tasks and selective attention in humans and primates [79–81] are decreased in schizophrenic patients with working memory deficits. These patients display a loss of gamma oscillation power and gamma oscillations are less tightly phase-locked to the task [82, 84, 85]. These changes might reflect functional alterations in the PV-positive basket cells, which contribute to the generation and regulation of the gamma oscillations that synchronise assemblies of pyramidal cells involved in a specific task [69, 72, 76–78, 83, 302]. In summary, multiple studies point to putative anomalies, either structural or functional, in PV-positive INs in the prefrontal cortex of schizophrenic patients.

5.3. Interneurons and Autism

Autism is a neurodevelopmental disorder combining impairments in socialization, communication, and restricted interests and/or stereotyped behaviors [294]. Autistic traits can be found in a variety of well-defined neurogenetic syndromes, including tuberous sclerosis [303, 304], fragile X syndrome [133, 134], and Rett syndrome [294]. In addition, nonsyndromic autism (re: without a clear underlying pathology, dysmorphic traits, or structural brain anomalies) has been associated with a variety of de novo copy number variants (CNVs) in large genome-wide association studies [141, 305–308], a finding which must be interpreted with caution [309]. However, the discovery of point mutations in genes encoding various synaptic scaffolding proteins in patients with nonsyndromic autism has begun to shed light on the pathophysiology of this disorder (recently reviewed in [309]). In particular, the discovery of mutations in postsynaptic neuroligins (NRL4X, NRL3) [135, 136], in other postsynaptic scaffolding proteins (SHANK2, SHANK3) [137–140, 310], in the presynaptic neurexins (NRXN1) [141, 142], and in fragile X mental retardation protein (FMR1 gene) suggest that dysfunction in the maintenance of excitatory synapses, synaptic plasticity, and long-term depression participate in the neurobiology of autism and that this might be rescued by metabotropic glutamatergic antagonists [151–154, 156, 311, 312].

In parallel, a dysfunction in GABAergic signalling has been postulated to contribute to the emergence of autistic behaviours. In fact, epilepsy is a frequent comorbidity of autism. Interictal epileptic activity is recorded on scalp EEG in up to 85% of autistic children, although seizures occur in only ~30% of patients [313, 314] (Table 2). This, together with the finding of decreased cortical GAD67/GAD65 expression in autistic patients' brains [143], has suggested that inhibitory dysfunction might play a role in subsets of autistic patients. Furthermore, polymorphisms in the Dlx1/2 genes have been associated with an increased susceptibility for autism [144] supporting the link between GABAergic anomalies and autism. In addition, nonsyndromic autism has been repeatedly associated with maternal chromosomal duplications in the 15q11-13 region [145, 146], which includes multiple genes encoding various GABA_A receptor subunits (GABRA5, GABRG3, and GABRB3). Interestingly, MecP2, a transcription factor that broadly regulates gene expression by binding methylated CPG islands and which is responsible for the majority of cases of Rett syndrome (see next section), also exerts epigenetic control over this chromosomal region [157]. The loss of MecP2 results in dysregulation of multiple genes, including the downregulation of GABRB3. Furthermore, the loss of MecP2 is particularly detrimental to interneurons and a conditional MecP2 ablation in GABAergic neurons in mice was recently shown to recapitulate most of the behavioral anomalies associated with Rett syndrome, including autistic-like behavior [158].

Finally, another well-characterised mouse model of autism, the uPAR^−/− mouse, displays a spatially selective defect in interneuron migration, such that the frontoparietal cortices of these mice show 50% less calbindin-positive interneurons (with a near absence of PV cells) whereas more caudal cortices are spared [11, 12]. These mice display autistic-like behaviors with increased anxiety and altered socialisation, as well as interictal epileptiform EEG activity and an increased susceptibility to seizures [11, 12]. uPAR encodes an urokinase plasminogen activator which is required for the proper processing of the hepatocyte growth factor (HGF). In turn, HGF, through its receptor MET, has been shown to be a critical motogen for interneuron migration and is able to rescue the interneuron migration defect and seizure susceptibility of uPAR^−/− mice [159, 160]. Interestingly, polymorphisms in the MET promoter have recently been described to confer an increased susceptibility to autism and this gene is included in one of the genomic sequences linked to autism susceptibility (7q31) [149, 150]. Autism is a complex disorder and alterations in other GABAergic circuits, including the striatocortical circuits, likely contribute to this behavioural phenotype. Indeed, an interneuron-selective ablation of MET results in decreased cortical PV cells, but massively increased dorsal striatal PV interneurons, leading to a disruption in striatal-mediated procedural and reversal learning [161]. Nonetheless, cortical and hippocampal GABAergic deficits certainly play a role in some of the cognitive-behavioral manifestations of autism, as well as in the associated susceptibility to seizures.

5.4. Interneurons and Epilepsy

Perhaps one of the most intuitive consequences of interneuron dysfunction is the development of epilepsy. Multiple mouse models carrying interneuronopathies have been shown to develop seizures [22, 28, 57, 63, 206, 207, 221]. In parallel, various reports point to probable GABAergic interneuron dysfunction in developmental and symptomatic (posttraumatic or poststatus epilepticus) epileptic disorders in humans [315–318]. In most situations, early developmental interneuron anomalies might contribute to seizure disorders both by altering the normal development of cortical circuits, as detailed above, and by failing to provide the acute inhibition required to control excessive excitation in the mature network. Paradoxically, in a state of chronic excitation, INs have been shown to contribute actively to ictogenesis when GABA becomes depolarizing due to the failure of chloride extrusion from damaged neurons [319, 320]. Therefore, both a primary dysfunction of GABAergic inhibitory transmission and a secondary switch to excitatory GABAergic transmission could contribute to the pathogenesis of epilepsy. Understanding the molecular mechanisms governing interneuron development, maturation, and normal function would therefore be very informative in our quest to comprehend human epileptic disorders.

Epilepsy is a heterogeneous disorder, and most cases are symptomatic of focal or widespread CNS lesions (e.g., malformations, tumors, infections, trauma, strokes, hypoxia, etc.). INs dysfunctions might contribute to seizure disorders following such insults, as suggested by the finding of limbic interneuronal loss after brain trauma or prolonged seizures [321–324]. Hippocampal somatostatin-positive interneurons appear to be particularly sensitive to seizure-induced damage as demonstrated in animal models of drug-induced epilepsy [13, 108, 324, 325], as well as in patients with chronic temporal lobe epilepsy [326]. This might point to a more selective vulnerability of this cell type which could be amendable to neuroprotective therapies. A loss of hippocampal PV cells [327] and alterations in the axonal projections of PV-positive chandelier cells have also been reported in patients with chronic epilepsy [316, 325, 328, 329]. Although it is not clear if these changes are the cause or the consequence of repeated seizures [330, 331], they probably contribute to the chronicity of the disease.

5.5. Interneurons in Genetic Developmental Epilepsies

Perhaps most interestingly, GABAergic interneuron dysfunction might contribute to a subset of genetic developmental epilepsies. In those cryptogenic epilepsies where no apparent etiology is found on examination or imaging (re: no dysmorphic traits or neurocutaneous stigma and normal brain CT/MRI), but where patients present clear neurological dysfunction as episodic seizures with or without interictal cognitive impairment, an underlying circuit dysfunction is postulated. These patients with severe developmental epilepsies (i.e., Ohtahara syndrome, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, etc.) are rarely amendable to surgical interventions, and only few reports of neuropathological examination of surgical or postmortem specimens are available. In most cases of West syndrome, the neuropathological evaluation reveals either focal cortical malformations or diffuse brain damage [332–335] but it is found to be “normal” in up to 45% of cases [336]. Nonetheless, functional inhibitory defects with disrupted GABA_AR function or immature patterns of GABA_AR subunit expression have been demonstrated in some cases of infantile spasms [318, 337]. Such inhibitory defects might arise as a consequence of genetic mutations that disrupt genes critical for proper interneuron generation or function. For instance, mutations in the alpha1 subunit of the voltage-gated sodium channel Na_V 1.1 (SCN1A), the aristaless-related homeobox transcription factor (ARX), the cyclin-dependent kinase-like 5 (CDKL5), various GABA_A receptor subunits and in the alpha 1 subunit of the voltage-dependent P/Q-type Ca²⁺ channel (CACNA1A) have been described in patients with a variety of epileptic disorders and similar mutations have been shown to impair GABAergic signalling in rodents (Table 3).

The author is grateful to J. Hjerling-Leffler, J. Close, and S. Rossignol for their enlightening input in reviewing this paper. The author also wishes to thank the Fond de recherche en santé du Québec (FRSQ), the U. de Montréal, and the Centre de recherche de l'Hôpital Ste-Justine for their support.