GABAergic Interneurons Research Articles

Long-term effects of low prenatal alcohol exposure on GABAergic interneurons of the murine posterior parietal cortex.

Fetal alcohol spectrum disorders (FASDs) are characterized by a wide range of physical, cognitive, and behavioral impairments that occur throughout the lifespan. Prenatal alcohol exposure (PAE) can lead to adult impairments in cognitive control behaviors mediated by the posterior parietal cortex (PPC). The PPC plays a fundamental role in the performance of response tasks in both primates and rodents, specifically when choices between similar target and nontarget stimuli are required. Furthermore, the PPC is reciprocally connected with other cortical areas. Despite the extensive literature investigating the molecular mechanisms underlying PAE impairments in cognitive functions mediated by cortical areas, little is known regarding the long-term effects of PAE on PPC development and function. Here, we examined changes in the cellular organization of GABAergic interneurons and their function in PPC using behaviorally naïve control and PAE mice. We used a limited access model of PAE in which C57BL/6J females were exposed to a solution of 10% (w/v) ethanol and 0.066% (w/V) saccharin for 4 h/day throughout gestation. Using high-throughput fluorescent microscopy, we quantified the levels of GABAergic interneurons in the PPC of adult PAE and control offspring. In a separate cohort, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) using whole-cell patch clamp recordings from PPC layer 5 pyramidal neurons. PAE led to a significant overall reduction of parvalbumin-expressing GABAergic interneurons in PAE mice regardless of sex. Somatostatin- and calretinin-expressing GABAergic interneurons were not affected. Interestingly, PAE did not modulate sIPSC amplitude or frequency. These results suggest that impairments in cognitive control observed in FASD may be due to the significant reduction of parvalbumin-expressing GABAergic interneurons in the PPC. PAE animals may show compensatory changes in GABAergic function following developmental reduction of these interneurons.

Electroacupuncture exerts prolonged analgesic and neuroprotective effects in a persistent dental pain model induced by multiple dental pulp injuries: GABAergic interneurons-astrocytes interaction.

Pain within the trigeminal system, particularly dental pain, is poorly understood. This study aimed to determine whether single or multiple dental pulp injuries induce persistent pain, its association with trigeminal central nociceptive pathways and whether electroacupuncture (EA) provides prolonged analgesic and neuroprotective effects in a persistent dental pain model. Models of single dental pulp injury (SDPI) and multiple dental pulp injuries (MDPI) were used to induce trigeminal neuropathic pain. The signs of dental pain-related behavior were assessed using the mechanical head withdrawal threshold (HWT). Immunofluorescence and western blot protocols were used to monitor astrocyte activation, changes in apoptosis-related proteins, and GABAergic interneuron plasticity. SDPI mice exhibited an initial marked decrease in HWT from days one to 14, followed by progressive recovery from days 21 to 42. From days 49 to 70, the HWT increased and returned to the control values. In contrast, MDPI mice showed a persistent decrease in HWT from days one to 70. MDPI increased glial fibrillary acidic protein (GFAP) and decreased glutamine synthetase (GS) and glutamate transporter-1 (GLT1) expression in the Vi/Vc transition zone of the brainstem on day 70, whereas no changes in astrocytic markers were observed on day 70 after SDPI. Increased expression of cleaved cysteine-aspartic protease-3 (cleaved caspase-3) and Bcl-2-associated X protein (Bax), along with decreased B-cell lymphoma/leukemia 2 (Bcl-2), were observed at day 70 after MDPI but not after SDPI. The downregulation of glutamic acid decarboxylase (GAD65) expression was observed on day 70 only after MDPI. The effects of MDPI-induced lower HWT from days one to 70 were attenuated by 12 sessions of EA treatment (days one to 21 after MDPI). Changes in astrocytic GFAP, GS, and GLT-1, along with cleaved caspase-3, Bax, Bcl-2, and GAD65 expression observed 70 days after MDPI, were reversed by EA treatment. The results suggest that persistent dental pain in mice was induced by MDPI but not by SDPI. This effect was associated with trigeminal GABAergic interneuron plasticity along with morphological and functional changes in astrocytes. EA exerts prolonged analgesic and neuroprotective effects that might be associated with the modulation of neuron-glia crosstalk mechanisms.

The role of subicular VIP-expressing interneurons on seizure dynamics in the intrahippocampal kainic acid model of temporal lobe epilepsy

The subiculum, a key output region of the hippocampus, is increasingly recognized as playing a crucial role in seizure initiation and spread. The subiculum consists of glutamatergic pyramidal cells, which show alterations in intrinsic excitability in the course of epilepsy, and multiple types of GABAergic interneurons, which exhibit varying characteristics in epilepsy. In this study, we aimed to assess the role of the vasoactive intestinal peptide interneurons (VIP-INs) of the ventral subiculum in the pathophysiology of temporal lobe epilepsy. We observed that an anatomically restricted inhibition of VIP-INs of the ventral subiculum was sufficient to reduce seizures in the intrahippocampal kainic acid model of epilepsy, changing the circadian rhythm of seizures, emphasizing the critical role of this small cell population in modulating TLE. As we expected, permanent unilateral or bilateral silencing of VIP-INs of the ventral subiculum in non-epileptic animals did not induce seizures or epileptiform activity. Interestingly, transient activation of VIP-INs of the ventral subiculum was enough to increase the frequency of seizures in the acute seizure model. Our results offer new perspectives on the crucial involvement of VIP-INs of the ventral subiculum in the pathophysiology of TLE. Given the observed predominant disinhibitory role of the VIP-INs input in subicular microcircuits, modifications of this input could be considered in the development of therapeutic strategies to improve seizure control.

MicroRNA-218 instructs proper assembly of hippocampal networks.

The assembly of the mammalian brain is orchestrated by temporally coordinated waves of gene expression. Post-transcriptional regulation by microRNAs (miRNAs) is a key aspect of this program. Indeed, deletion of neuron-enriched miRNAs induces strong developmental phenotypes, and miRNA levels are altered in patients with neurodevelopmental disorders. However, the mechanisms used by miRNAs to instruct brain development remain largely unexplored. Here, we identified miR-218 as a critical regulator of hippocampal assembly. MiR-218 is highly expressed in the hippocampus and enriched in both excitatory principal neurons (PNs) and GABAergic inhibitory interneurons (INs). Early life inhibition of miR-218 results in an adult brain with a predisposition to seizures. Changes in gene expression in the absence of miR-218 suggest that network assembly is impaired. Indeed, we find that miR-218 inhibition results in the disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines, and altered intrinsic membrane excitability. Conditional knockout of Mir218-2 in INs, but not PNs, is sufficient to recapitulate long-term instability. Finally, de-repressing Kif21b and Syt13, two miR-218 targets, phenocopies the effects on early synchronous network activity induced by miR-218 inhibition. Taken together, the data suggest that miR-218 orchestrates formative events in PNs and INs to produce stable networks.

A class-specific effect of dysmyelination on the excitability of hippocampal interneurons.

The role of myelination for axonal conduction is well-established in projection neurons but little is known about its significance in GABAergic interneurons. Myelination is discontinuous along interneuron axons and the mechanisms controlling myelin patterning and segregation of ion channels at the nodes of Ranvier have not been elucidated. Protein 4.1B is implicated in the organization of the nodes of Ranvier as a linker between paranodal and juxtaparanodal membrane proteins to the spectrin cytoskeleton. In the present study, 4.1B KO mice are used as a genetic model to analyze the functional role of myelin in Lhx6-positive parvalbumin (PV) and somatostatin (SST) neurons, two major classes of GABAergic neurons in the hippocampus. We show that 4.1B-deficiency induces disruption of juxtaparanodal K+ channel clustering and mislocalization of nodal or heminodal Na+ channels. Strikingly, 4.1B-deficiency causes loss of myelin in GABAergic axons in the hippocampus. In particular, stratum oriens SST cells display severe axonal dysmyelination and a reduced excitability. This reduced excitability is associated with a decrease in occurrence probability of small amplitude synaptic inhibitory events on pyramidal cells. In contrast, stratum pyramidale fast-spiking PV cells do not appear affected. In conclusion, our results indicate a class-specific effect of dysmyelination on the excitability of hippocampal interneurons associated with a functional alteration of inhibitory drive.

GABAAR-mediated tonic inhibition differentially modulates intrinsic excitability of VIP- and SST- expressing interneurons in layers 2/3 of the somatosensory cortex.

Extrasynaptic GABAA receptors (GABAARs) mediating tonic inhibition are thought to play an important role in the regulation of neuronal excitability. However, little is known about a cell type-specific tonic inhibition in molecularly distinctive types of GABAergic interneurons in the mammalian neocortex. Here, we used whole-cell patch-clamp techniques in brain slices prepared from transgenic mice expressing red fluorescent protein (TdTomato) in vasoactive intestinal polypeptide- or somatostatin- positive interneurons (VIP-INs and SST-INs, respectively) to investigate tonic and phasic GABAAR-mediated inhibition as well as effects of GABAA inhibition on intrinsic excitability of these interneurons in layers 2/3 (L2/3) of the somatosensory (barrel) cortex. We found that tonic inhibition was stronger in VIP-INs compared to SST-INs. Contrary to the literature data, tonic inhibition in SST-INs was comparable to pyramidal (Pyr) neurons. Next, tonic inhibition in both interneuron types was dependent on the activity of delta subunit-containing GABAARs. Finally, the GABAAR activity decreased intrinsic excitability of VIP-INs but not SST-INs. Altogether, our data indicate that GABAAR-mediated inhibition modulates neocortical interneurons in a type-specific manner. In contrast to L2/3 VIP-INs, intrinsic excitability of L2/3 SST-INs is immune to the GABAAR-mediated inhibition.

Temporal manipulation of the Scn1a gene reveals its essential role in adult brain function.

Dravet syndrome is a severe epileptic encephalopathy, characterized by drug-resistant epilepsy, severe cognitive and behavioural deficits, with increased risk of sudden unexpected death (SUDEP). It is caused by haploinsufficiency of SCN1A gene encoding for the α-subunit of the voltage-gated sodium channel Nav1.1. Therapeutic approaches aiming to upregulate the healthy copy of SCN1A gene to restore its normal expression levels are being developed. However, whether Scn1a gene function is required only during a specific developmental time-window or, alternatively, if its physiological expression is necessary in adulthood is untested up to now. We induced Scn1a gene haploinsufficiency at two ages spanning postnatal brain development (P30 and P60) and compared the phenotypes of those mice to Scn1a perinatally induced mice (P2), recapitulating all deficits of Dravet mice. Induction of heterozygous Nav1.1 mutation at P30 and P60 elicited susceptibility to the development of both spontaneous and hyperthermia-induced seizures and SUDEP rates comparable to P2-induced mice, with symptom onset accompanied by the characteristic GABAergic interneuron dysfunction. Finally, delayed Scn1a haploinsufficiency induction provoked hyperactivity, anxiety and social attitude impairment at levels comparable to age matched P2-induced mice, while it was associated with a better cognitive performance, with P60-induced mice behaving like the control group. Our data show that maintenance of physiological levels of Nav1.1 during brain development is not sufficient to prevent Dravet symptoms and that long-lasting restoration of Scn1a gene expression would be required to grant optimal clinical benefit in patients with Dravet syndrome.

Microglia trigger the structural plasticity of GABAergic neurons in the hippocampal CA1 region of a lipopolysaccharide-induced neuroinflammation model

It is well-established that microglia-mediated neuroinflammatory response involves numerous neuropsychiatric and neurodegenerative diseases. While the role of microglia in excitatory synaptic transmission has been widely investigated, the impact of innate immunity on the structural plasticity of GABAergic inhibitory synapses is not well understood. To investigate this, we established an inflammation model using lipopolysaccharide (LPS) and observed a prolonged microglial response in the hippocampal CA1 region of mice, which was associated with cognitive deficits in the open field test, Y-maze test, and novel object recognition test. Furthermore, we found an increased abundance of GABAergic interneurons and GABAergic synapse formation in the hippocampal CA1 region. The cognitive impairment caused by LPS injection could be reversed by blocking GABA receptor activity with (−)-Bicuculline methiodide. These findings suggest that the upregulation of GABAergic synapses induced by LPS-mediated microglial activation leads to cognitive dysfunction. Additionally, the depletion of microglia by PLX3397 resulted in a decrease in GABAergic interneurons and GABAergic inhibitory synapses, which blocked the cognitive decline induced by LPS. In conclusion, our findings indicate that excessive reinforcement of GABAergic inhibitory synapse formation via microglial activation contributes to LPS-induced cognitive impairment.

Enhanced expression of parvalbumin and perineuronal nets in the medial prefrontal cortex after extended-access cocaine self-administration in rats.

The medial prefrontal cortex (mPFC) drives cocaine-seeking behaviour in rodent models of cocaine use disorder. Parvalbumin (PV)-containing GABAergic interneurons powerfully control the output of the mPFC, yet few studies have focused on how these neurons modulate cocaine-seeking behaviour. Most PV neurons are surrounded by perineuronal nets (PNNs), which regulate the firing of PV neurons. We examined staining intensity and number of PV and PNNs after long-access (6h/day) cocaine self-administration in rats followed by either 8-10days extinction ± cue-induced reinstatement or short-term (1-2days) or long-term (30-31 days) abstinence ± cue-induced reinstatement. The intensity of PNNs was increased in the prelimbic and infralimbic PFC after long-term abstinence in the absence of cue reinstatement and after cue reinstatement following both daily extinction sessions and after a 30-day abstinence period. PV intensity was increased after 30 days of abstinence in the prelimbic but not infralimbic PFC. Enzymatic removal of PNNs with chondroitinase ABC (ABC) in the prelimbic PFC did not prevent incubation of cue-induced reinstatement but decreased cocaine-seeking behaviour at both 2 and 31 days of abstinence, and this decrease at 31 days was accompanied by reduced c-Fos levels in the prelimbic PFC. Increases in PNN intensity have generally been associated with the loss of plasticity, suggesting that the persistent and chronic nature of cocaine use disorder may in part be attributed to long-lasting increases in PNN intensity that reduce the ability of stimuli to alter synaptic input to underlying PV neurons.

Human pallial MGE-type GABAergic interneuron cell therapy for chronic focal epilepsy.

Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy. One-third of patients have drug-refractory seizures and are left with suboptimal therapeutic options such as brain tissue-destructive surgery. Here, we report the development and characterization of a cell therapy alternative for drug-resistant MTLE, which is derived from a human embryonic stem cell line and comprises cryopreserved, post-mitotic, medial ganglionic eminence (MGE) pallial-type GABAergic interneurons. Single-dose intrahippocampal delivery of the interneurons in a mouse model of chronic MTLE resulted in consistent mesiotemporal seizure suppression, with most animals becoming seizure-free and surviving longer. The grafted interneurons dispersed locally, functionally integrated, persisted long term, and significantly reduced dentate granule cell dispersion, a pathological hallmark of MTLE. These disease-modifying effects were dose-dependent, with a broad therapeutic range. No adverse effects were observed. These findings support an ongoing phase 1/2 clinical trial (NCT05135091) for drug-resistant MTLE.

Binge-like ethanol exposure during the brain growth spurt disrupts the function of retrosplenial cortex-projecting anterior thalamic neurons in adolescent mice

Ethanol (EtOH) exposure during late pregnancy leads to enduring impairments in learning and memory that may stem from damage to components of the posterior limbic memory system, including the retrosplenial cortex (RSC) and anterior thalamic nuclei (ATN). In rodents, binge-like EtOH exposure during the first week of life (equivalent to the third trimester of human pregnancy) triggers apoptosis in these brain regions. We hypothesized that this effect induces long-lasting alterations in the function of RSC-projecting ATN neurons. To test this hypothesis, vesicular GABA transporter-Venus mice (expressing fluorescently tagged GABAergic interneurons) were subjected to binge-like EtOH vapor exposure on postnatal day (P) 7. This paradigm activated caspase 3 in the anterodorsal (AD), anteroventral (AV), and reticular thalamic nuclei at P7 but did not reduce neuronal density in these areas at P60-70. At P40-60, we injected red retrobeads into the RSC and performed patch-clamp slice electrophysiological recordings from retrogradely labeled neurons in the AD and AV nuclei 3–4 days later. We found significant effects of treatment on instantaneous action potential (AP) frequency and AP overshoot, as well as sex × treatment interactions for AP threshold and overshoot in AD neurons. A sex × treatment interaction was detected for AP number in AV neurons. EtOH exposure also reduced the frequency and amplitude of spontaneous excitatory postsynaptic currents and increased the charge transfer of spontaneous inhibitory postsynaptic currents. These results highlight a novel cellular mechanism that could contribute to the lasting learning and memory deficits associated with developmental EtOH exposure.

Psychiatric risk gene Transcription Factor 4 (TCF4) regulates the density and connectivity of distinct inhibitory interneuron subtypes.

Transcription factor 4 (TCF4) is a basic helix-loop-helix transcription factor that is implicated in a variety of psychiatric disorders including autism spectrum disorder (ASD), major depression, and schizophrenia. Autosomal dominant mutations in TCF4 are causal for a specific ASD called Pitt-Hopkins Syndrome (PTHS). However, our understanding of etiological and pathophysiological mechanisms downstream of TCF4 mutations is incomplete. Single cell sequencing indicates TCF4 is highly expressed in GABAergic interneurons (INs). Here, we performed cell-type specific expression analysis (CSEA) and cellular deconvolution (CD) on bulk RNA sequencing data from 5 different PTHS mouse models. Using CSEA we observed differentially expressed genes (DEGs) were enriched in parvalbumin expressing (PV+) INs and CD predicted a reduction in the PV+ INs population. Therefore, we investigated the role of TCF4 in regulating the development and function of INs in the Tcf4+/tr mouse model of PTHS. In Tcf4+/tr mice, immunohistochemical (IHC) analysis of subtype-specific IN markers and reporter mice identified reductions in PV+, vasoactive intestinal peptide (VIP+), and cortistatin (CST+) expressing INs in the cortex and cholinergic (ChAT+) INs in the striatum, with the somatostatin (SST+) IN population being spared. The reduction of these specific IN populations led to cell-type specific alterations in the balance of excitatory and inhibitory inputs onto PV+ and VIP+ INs and excitatory pyramidal neurons within the cortex. These data indicate TCF4 is a critical regulator of the development of specific subsets of INs and highlight the inhibitory network as an important source of pathophysiology in PTHS.

Construction of a Hierarchical Organization in Semantic Memory: A Model Based on Neural Masses and Gamma-Band Synchronization

Semantic memory is characterized by a hierarchical organization of concepts based on shared properties. However, this aspect is insufficiently dealt with in recent neurocomputational models. Moreover, in many cognitive problems that exploit semantic memory, gamma-band synchronization can be relevant in favoring information processing and feature binding. In this work, we propose an attractor network model of semantic memory. Each computational unit, coding for a different feature, is described with a neural mass circuit oscillating in the gamma range. The model is trained with an original nonsymmetric Hebb rule based on a presynaptic gating mechanism. After training, the network creates a taxonomy of categories, distinguishes between subordinate and superordinate concepts, and discriminates between salient and marginal features. Examples are provided concerning a fourteen-animal taxonomy, including several subcategories. A sensitivity analysis reveals the robustness of the network but also points out conditions leading to confusion among categories, similar to the one observed in dreaming and some neurological disorders. Finally, the analysis emphasizes the role of fast GABAergic interneurons and inhibitory-excitatory balance to allow the correct synchronization of features. The model represents an original attempt to deal with a hierarchical organization of objects in semantic memory and correlated patterns, still exploiting gamma-band synchronization to favor neural processing. The same ideas, introduced in a more sophisticated multilayer network, can deepen our knowledge of semantic memory organization in the brain. Finally, they can open new perspectives in quantitatively analyzing neurological disorders connected with distorted semantics.

Vibration-reduced anxiety-like behavior relies on ameliorating abnormalities of the somatosensory cortex and medial prefrontal cortex.

Abstract JOURNAL/nrgr/04.03/01300535-202406000-00040/inline-graphic1/v/2023-10-30T152229Z/r/image-tiff Tibetan singing bowls emit low-frequency sounds and produce perceptible harmonic tones and vibrations through manual tapping. The sounds the singing bowls produce have been shown to enhance relaxation and reduce anxiety. However, the underlying mechanism remains unclear. In this study, we used chronic restraint stress or sleep deprivation to establish mouse models of anxiety that exhibit anxiety-like behaviors. We then supplied treatment with singing bowls in a bottomless cage placed on the top of a cushion. We found that unlike in humans, the combination of harmonic tones and vibrations did not improve anxiety-like behaviors in mice, while individual vibration components did. Additionally, the vibration of singing bowls increased the level of N-methyl-D-aspartate receptor 1 in the somatosensory cortex and prefrontal cortex of the mice, decreased the level of γ-aminobutyric acid A (GABA) receptor α 1 subtype, reduced the level of CaMKII in the prefrontal cortex, and increased the number of GABAergic interneurons. At the same time, electrophysiological tests showed that the vibration of singing bowls significantly reduced the abnormal low-frequency gamma oscillation peak frequency in the medial prefrontal cortex caused by stress restraint pressure and sleep deprivation. Results from this study indicate that the vibration of singing bowls can alleviate anxiety-like behaviors by reducing abnormal molecular and electrophysiological events in somatosensory and medial prefrontal cortex.

Mechanisms of acupuncture-electroacupuncture on inflammatory pain.

Acupuncture, as a traditional treatment, has been extensively used in China for thousands of years. According to the World Health Organization (WHO), acupuncture is recommended for the treatment of 77 diseases. And sixteen of these diseases are related to inflammatory pain. As a combination of traditional acupuncture and modern electrotherapy, electroacupuncture (EA) has satisfactory analgesic effects on various acute and chronic pain. Because of its good analgesic effects and no side effects, acupuncture has been widely accepted all over the world. Despite the increase in the number of studies, the mechanisms via which acupuncture exerts its analgesic effects have not been conclusively established. A literature review of related research is of great significance to elaborate on its mechanisms and to inform on further research directions. We elucidated on its mechanisms of action on inflammatory pain from two levels: peripheral and central. It includes the mechanisms of acupuncture in the periphery (immune cells and neurons, purinergic pathway, nociceptive ion channel, cannabinoid receptor and endogenous opioid peptide system) and central nervous system (TPRV1, glutamate and its receptors, glial cells, GABAergic interneurons and signaling molecules ). In this review, we collected relevant recent studies to systematically explain the mechanisms of acupuncture in treating inflammatory pain, with a view to providing direction for future applications of acupuncture in inflammatory pain and promoting clinical development.

Perceptual learning deficits mediated by somatostatin releasing inhibitory interneurons of olfactory bulb in an early life stress mouse model

Early life adversity (ELA) causes aberrant functioning of neural circuits affecting the health of an individual. While ELA-induced behavioural disorders resulting from sensory and cognitive disabilities can be assessed clinically, the neural mechanisms need to be probed using animal models by employing multi-pronged experimental approaches. As ELA can alter sensory perception, we investigated the effect of early weaning on murine olfaction. By implementing go/no-go odour discrimination paradigm, we observed olfactory learning and memory impairments in early life stressed (ELS) male mice. As olfactory bulb (OB) circuitry plays a critical role in odour learning, we studied the plausible changes in the OB of ELS mice. Lowered c-Fos activity in the external plexiform layer and a reduction in the number of dendritic processes of somatostatin-releasing, GABAergic interneurons (SOM-INs) in the ELS mice led us to hypothesise the underlying circuit. We recorded reduced synaptic inhibitory feedback on mitral/tufted (M/T) cells, in the OB slices from ELS mice, explaining the learning deficiency caused by compromised refinement of OB output. The reduction in synaptic inhibition was nullified by the photo-activation of ChR2-expressing SOM-INs in ELS mice. The role of SOM-INs was revealed by learning-dependent refinement of Ca2+dynamics quantified by GCaMP6f signals, which was absent in ELS mice. Further, the causal role of SOM-INs involving circuitry was investigated by optogenetic modulation during the odour discrimination learning. Photo-activating these neurons rescued the ELA-induced learning deficits. Conversely, photo-inhibition caused learning deficiency in control animals, while it completely abolished the learning in ELS mice, confirming the adverse effects mediated by SOM-INs. Our results thus establish the role of specific inhibitory circuit in pre-cortical sensory area in orchestrating ELA-dependent changes.

Interneuron odyssey: molecular mechanisms of tangential migration.

Cortical GABAergic interneurons are critical components of neural networks. They provide local and long-range inhibition and help coordinate network activities involved in various brain functions, including signal processing, learning, memory and adaptative responses. Disruption of cortical GABAergic interneuron migration thus induces profound deficits in neural network organization and function, and results in a variety of neurodevelopmental and neuropsychiatric disorders including epilepsy, intellectual disability, autism spectrum disorders and schizophrenia. It is thus of paramount importance to elucidate the specific mechanisms that govern the migration of interneurons to clarify some of the underlying disease mechanisms. GABAergic interneurons destined to populate the cortex arise from multipotent ventral progenitor cells located in the ganglionic eminences and pre-optic area. Post-mitotic interneurons exit their place of origin in the ventral forebrain and migrate dorsally using defined migratory streams to reach the cortical plate, which they enter through radial migration before dispersing to settle in their final laminar allocation. While migrating, cortical interneurons constantly change their morphology through the dynamic remodeling of actomyosin and microtubule cytoskeleton as they detect and integrate extracellular guidance cues generated by neuronal and non-neuronal sources distributed along their migratory routes. These processes ensure proper distribution of GABAergic interneurons across cortical areas and lamina, supporting the development of adequate network connectivity and brain function. This short review summarizes current knowledge on the cellular and molecular mechanisms controlling cortical GABAergic interneuron migration, with a focus on tangential migration, and addresses potential avenues for cell-based interneuron progenitor transplants in the treatment of neurodevelopmental disorders and epilepsy.

Elevated susceptibility to exogenous seizure triggers and impaired interneuron excitability in a mouse model of Leigh syndrome epilepsy

Mutations in the NADH dehydrogenase (ubiquinone reductase) iron‑sulfur protein 4 (NDUFS4) gene, which encodes for a key structural subunit of the OXFOS complex I (CI), lead to the most common form of mitochondrial disease in children known as Leigh syndrome (LS). As in other mitochondrial diseases, epileptic seizures constitute one of the most significant clinical features of LS. These seizures are often very difficult to treat and are a sign of poor disease prognosis. Mice with whole-body Ndufs4 KO are a well-validated model of LS; they exhibit epilepsy and several other clinical features of LS. We have previously shown that mice with Ndufs4 KO in only GABAergic interneurons (Gad2-Ndufs4-KO) reproduce the severe epilepsy phenotype observed in the global KO mice. This observation indicated that these mice represent an excellent model of LS epilepsy isolated from other clinical manifestations of the disease. To further characterize this epilepsy phenotype, we investigated seizure susceptibility to selected exogenous seizure triggers in Gad2-Ndufs4-KO mice. Then, using electrophysiology, imaging, and immunohistochemistry, we studied the cellular, physiological, and neuroanatomical consequences of Ndufs4 KO in GABAergic interneurons. Homozygous KO of Ndufs4 in GABAergic interneurons leads to a prominent susceptibility to exogenous seizure triggers, impaired interneuron excitability and interneuron loss. Finally, we found that the hippocampus and cortex participate in the generation of seizure activity in Gad2-Ndufs4-KO mice. These findings further define the LS epilepsy phenotype and provide important insights into the cellular mechanisms underlying epilepsy in LS and other mitochondrial diseases.

Fear learning and aversive stimuli differentially change excitatory synaptic transmission in perisomatic inhibitory cells of the basal amygdala.

Inhibitory circuits in the basal amygdala (BA) have been shown to play a crucial role in associative fear learning. How the excitatory synaptic inputs received by BA GABAergic interneurons are influenced by memory formation, a network parameter that may contribute to learning processes, is still largely unknown. Here, we investigated the features of excitatory synaptic transmission received by the three types of perisomatic inhibitory interneurons upon cue-dependent fear conditioning and aversive stimulus and tone presentations without association. Acute slices were prepared from transgenic mice: one group received tone presentation only (conditioned stimulus, CS group), the second group was challenged by mild electrical shocks unpaired with the CS (unsigned unconditioned stimulus, unsigned US group) and the third group was presented with the CS paired with the US (signed US group). We found that excitatory synaptic inputs (miniature excitatory postsynaptic currents, mEPSCs) recorded in distinct interneuron types in the BA showed plastic changes with different patterns. Parvalbumin (PV) basket cells in the unsigned US and signed US group received mEPSCs with reduced amplitude and rate in comparison to the only CS group. Coupling the US and CS in the signed US group caused a slight increase in the amplitude of the events in comparison to the unsigned US group, where the association of CS and US does not take place. Excitatory synaptic inputs onto cholecystokinin (CCK) basket cells showed a markedly different change from PV basket cells in these behavioral paradigms: only the decay time was significantly faster in the unsigned US group compared to the only CS group, whereas the amplitude of mEPSCs increased in the signed US group compared to the only CS group. Excitatory synaptic inputs received by PV axo-axonic cells showed the least difference in the three behavioral paradigm: the only significant change was that the rate of mEPSCs increased in the signed US group when compared to the only CS group. These results collectively show that associative learning and aversive stimuli unpaired with CS cause different changes in excitatory synaptic transmission in BA perisomatic interneuron types, supporting the hypothesis that they play distinct roles in the BA network operations upon pain information processing and fear memory formation.

Id2 GABAergic interneurons comprise a neglected fourth major group of cortical inhibitory cells.

Cortical GABAergic interneurons (INs) represent a diverse population of mainly locally projecting cells that provide specialized forms of inhibition to pyramidal neurons and other INs. Most recent work on INs has focused on subtypes distinguished by expression of Parvalbumin (PV), Somatostatin (SST), or Vasoactive Intestinal Peptide (VIP). However, a fourth group that includes neurogliaform cells (NGFCs) has been less well characterized due to a lack of genetic tools. Here, we show that these INs can be accessed experimentally using intersectional genetics with the gene Id2. We find that outside of layer 1 (L1), the majority of Id2 INs are NGFCs that express high levels of neuropeptide Y (NPY) and exhibit a late-spiking firing pattern, with extensive local connectivity. While much sparser, non-NGFC Id2 INs had more variable properties, with most cells corresponding to a diverse group of INs that strongly expresses the neuropeptide CCK. In vivo, using silicon probe recordings, we observed several distinguishing aspects of NGFC activity, including a strong rebound in activity immediately following the cortical down state during NREM sleep. Our study provides insights into IN diversity and NGFC distribution and properties, and outlines an intersectional genetics approach for further study of this underappreciated group of INs.