GABAergic precursor transplantation into the prefrontal cortex prevents phencyclidine-induced cognitive deficits

Phencyclidine (PCP) is a noncompetitive NMDA receptor antagonist, and it induces schizophreniform cognitive deficits in healthy humans and similar cognitive deficits in rodents. Although the PCP-induced cognitive deficits appear to be accompanied and possibly caused by dysfunction of GABAergic inhibitory interneurons in the prefrontal cortex (PFC), the potential benefit(s) of GABAergic interneuron manipulations on PCP-induced cognitive deficits remains unexplored. In this study we show that when embryonic medial ganglionic eminence (MGE) cells, many of which differentiate into cortical GABAergic interneurons in situ, were grafted into the medial PFC (mPFC) of neonatal mice, they differentiated into a specific class of GABAergic interneurons and became functionally integrated into the host neuronal circuitry in adults. Prior MGE cell transplantation into the mPFC significantly prevented the induction of cognitive and sensory-motor gating deficits by PCP. The preventive effects were not reproduced by either transplantation of cortical projection neuron precursors into the mPFC or transplantation of MGE cells into the occipital cortex. The preventive effects of MGE cell transplantation into the mPFC were accompanied by activation of callosal projection neurons in the mPFC. These findings suggest that increasing GABAergic interneuron precursors in the PFC may contribute to the development of a cell-based approach as a novel means of modulating the PFC neuronal circuitry and preventing schizophreniform cognitive deficits.     

Impaired and repaired inhibitory circuits in the epileptic human hippocampus

This review focuses on the epileptic human temporal lobe, primarily on recent findings related to changes in hippocampal GABAergic interneuron circuits that have a central role in epileptogenesis. Relying on correlations to animal studies, we provide a functional interpretation of the different changes in perisomatic inhibition (controlling output synchrony) and dendritic inhibition (controlling input plasticity), and the potential consequences of the loss of interneuron-selective interneurons. The highly heterogeneous, but specific, alterations of GABAergic interneuron circuits have important implications for the pharmacotherapy of epilepsy.     

Interneuron Development and Epilepsy: Early Genetic Defects Cause Long-Term Consequences in Seizures and Susceptibility

Errors in the generation of the inhibitory GABAergic interneurons of the cerebral cortex and hippocampus have variable consequences. Studies of the molecular pathways of interneuron development reveal genes that are associated with human epilepsies. Animal models of gene variants exhibit seizures and abnormal electroencephalographic activity, providing unique models for discovering better treatments for individual forms of epilepsy.     

Differential gene expression in migrating cortical interneurons during mouse forebrain development

γ‐Aminobutyric acid (GABA)ergic interneurons play a vital role in modulating the activity of the cerebral cortex, and disruptions to their function have been linked to neurological disorders such as schizophrenia and epilepsy. These cells originate in the ganglionic eminences (GE) of the ventral telencephalon and undergo tangential migration to enter the cortex. Currently, little is known about the signaling mechanisms that regulate interneuron migration. We therefore performed a microarray analysis comparing the changes in gene expression between the GABAergic interneurons that are actively migrating into the cortex with those in the GE. We were able to isolate pure populations of GABAergic cells by fluorescence‐activated cell sorting of cortex and GE from embryonic brains of glutamate decarboxylase 67 (GAD67)‐green fluorescent protein (GFP) transgenic mice. Our microarray analysis identified a number of novel genes that were upregulated in migrating cortical interneurons at both E13.5 and E15.5. Many of these genes have previously been shown to play a role in cell migration of both neuronal and non‐neuronal cell types. In addition, several of the genes identified are involved in the regulation of migratory processes, such as neurite outgrowth, cell adhesion, and remodeling of the actin cytoskeleton and microtubule network. Moreover, quantitative polymerase chain reaction and in situ hybridization analyses confirmed that the expression of some of these genes is restricted to cortical interneurons. These data therefore provide a framework for future studies aimed at elucidating the complexities of interneuron migration and, in turn, may reveal important genes that are related to the development of specific neurological disorders. J. Comp. Neurol. 518:1232–1248, 2010. © 2009 Wiley‐Liss, Inc.     

Morpho‐physiological criteria divide dentate gyrus interneurons into classes

GABAergic inhibitory interneurons control fundamental aspects of neuronal network function. Their functional roles are assumed to be defined by the identity of their input synapses, the architecture of their dendritic tree, the passive and active membrane properties and finally the nature of their postsynaptic targets. Indeed, interneurons display a high degree of morphological and physiological heterogeneity. However, whether their morphological and physiological characteristics are correlated and whether interneuron diversity can be described by a continuum of GABAergic cell types or by distinct classes has remained unclear. Here we perform a detailed morphological and physiological characterization of GABAergic cells in the dentate gyrus, the input region of the hippocampus. To achieve an unbiased and efficient sampling and classification we used knock‐in mice expressing the enhanced green fluorescent protein (eGFP) in glutamate decarboxylase 67 (GAD67)‐positive neurons and performed cluster analysis. We identified five interneuron classes, each of them characterized by a distinct set of anatomical and physiological parameters. Cross‐correlation analysis further revealed a direct relation between morphological and physiological properties indicating that dentate gyrus interneurons fall into functionally distinct classes which may differentially control neuronal network activity. © 2013 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Cracking down on inhibition: selective removal of GABAergic interneurons from hippocampal networks

Inhibitory (GABAergic) interneurons entrain assemblies of excitatory principal neurons to orchestrate information processing in the hippocampus. Disrupting the dynamic recruitment as well as the temporally precise activity of interneurons in hippocampal circuitries can manifest in epileptiform seizures, and impact specific behavioral traits. Despite the importance of GABAergic interneurons during information encoding in the brain, experimental tools to selectively manipulate GABAergic neurotransmission are limited. Here, we report the selective elimination of GABAergic interneurons by a ribosome inactivation approach through delivery of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs) in vitro as well as in the mouse and rat hippocampus in vivo. We demonstrate the selective loss of GABAergic--but not glutamatergic--synapses, reduced GABA release, and a shift in excitation/inhibition balance in mixed cultures of hippocampal neurons exposed to SAVAs. We also show the focal and indiscriminate loss of calbindin(+), calretinin(+), parvalbumin/system A transporter 1(+), somatostatin(+), vesicular glutamate transporter 3 (VGLUT3)/cholecystokinin/CB(1) cannabinoid receptor(+) and neuropeptide Y(+) local-circuit interneurons upon SAVA microlesions to the CA1 subfield of the rodent hippocampus, with interneuron debris phagocytosed by infiltrating microglia. SAVA microlesions did not affect VGLUT1(+) excitatory afferents. Yet SAVA-induced rearrangement of the hippocampal circuitry triggered network hyperexcitability associated with the progressive loss of CA1 pyramidal cells and the dispersion of dentate granule cells. Overall, our data identify SAVAs as an effective tool to eliminate GABAergic neurons from neuronal circuits underpinning high-order behaviors and cognition, and whose manipulation can recapitulate pathogenic cascades of epilepsy and other neuropsychiatric illnesses.     

Cortical and thalamic inputs exert cell type-specific feedforward inhibition on striatal GABAergic interneurons

The classical view of striatal GABAergic interneuron function has been that they operate as largely independent, parallel, feedforward inhibitory elements providing inhibitory inputs to spiny projection neurons (SPNs). Much recent evidence has shown that the extrinsic innervation of striatal interneurons is not indiscriminate but rather very specific, and that striatal interneurons are themselves interconnected in a cell type-specific manner. This suggests that the ultimate effect of extrinsic inputs on striatal neuronal activity depends critically on synaptic interactions within interneuronal circuitry. Here, we compared the cortical and thalamic input to two recently described subtypes of striatal GABAergic interneurons, tyrosine hydroxylase-expressing interneurons (THINs), and spontaneously active bursty interneurons (SABIs) using transgenic TH-Cre and Htr3a-Cre mice of both sexes. Our results show that both THINs and SABIs receive strong excitatory input from the motor cortex and the thalamic parafascicular nucleus. Cortical optogenetic stimulation also evokes disynaptic inhibitory GABAergic responses in THINs but not in SABIs. In contrast, optogenetic stimulation of the parafascicular nucleus induces disynaptic inhibitory responses in both interneuron populations. However, the short-term plasticity of these disynaptic inhibitory responses is different suggesting the involvement of different intrastriatal microcircuits. Altogether, our results point to highly specific interneuronal circuits that are selectively engaged by different excitatory inputs.     

Development of Cerebellar GABAergic Interneurons: Origin and Shaping of the “Minibrain” Local Connections

The cerebellar circuits comprise a limited number of neuronal phenotypes embedded in a defined cytoarchitecture and generated according to specific spatio-temporal patterns. The local GABAergic network is composed of several interneuron phenotypes that play essential roles in information processing by modulating the activity of cerebellar cortical inputs and outputs. A major issue in the study of cerebellar development is to understand the mechanisms that underlie the generation of different interneuron classes and regulate their placement in the cerebellar architecture and integration in the cortico-nuclear network. Recent findings indicate that the variety of cerebellar interneurons derives from a single population of multipotent progenitors whose fate choices are determined by instructive environmental information. Such a strategy, which is unique for the cerebellum along the neuraxis, allows great flexibility in the control of the quality and quantity of GABAergic interneurons that are produced, thus facilitating the adaptive shaping of the cerebellar network to specific functional demands.     

Selective plasticity of hippocampal GABAergic interneuron populations following kindling of different brain regions

The vulnerability and plasticity of hippocampal GABAergic interneurons is a topic of broad interest and debate in the field of epilepsy. In this experiment, we used the electrical kindling model of epilepsy to determine whether seizures that originate in different brain regions have differential effects on hippocampal interneuron subpopulations. Long‐Evans rats received 99 electrical stimulations of the hippocampus, amygdala, or caudate nucleus, followed by sacrifice and immunohistochemical or western blot analyses. We analyzed markers of dendritic (somatostatin), perisomatic (parvalbumin), and interneuron‐selective (calretinin) inhibition, as well as an overall indicator (GAD67) of interneuron distribution across all major hippocampal subfields. Our results indicate that kindling produces selective effects on the number and morphology of different functional classes of GABAergic interneurons. In particular, limbic kindling appears to enhance dendritic inhibition, indicated by a greater number of somatostatin‐immunoreactive (‐ir) cells in the CA1 pyramidal layer and robust morphological sprouting in the dentate gyrus. We also found a reduction in the number of interneuron‐selective calretinin‐ir cells in the dentate gyrus of hippocampal‐kindled rats, which suggests a possible reduction of synchronized dendritic inhibition. In contrast, perisomatic inhibition indicated by parvalbumin immunoreactivity appears to be largely resilient to the effects of kindling. Finally, we found a significant induction in the number of GAD67‐cells in caudate‐kindled rats in the dentate gyrus and CA3 hippocampal subfields. Taken together, our results demonstrate that kindling has subfield‐selective effects on the different functional classes of hippocampal GABAergic interneurons. J. Comp. Neurol. 525:389–406, 2017. © 2016 Wiley Periodicals, Inc.     

Disruption of Interneuron Development

Summary:  Disruption of gamma-aminobutyric acid (GABAergic) interneuron development during the embryonic and early postnatal periods can have profound neurological and behavioral consequences. Hepatocyte growth factor/scatter factor (HGF/SF) has been identified as an important molecular cue that may guide the movement of interneurons from their birthplace in the ganglionic eminences (GE) to their final resting place in the neocortex. In vitro studies demonstrate that decreased HGF/SF bioactivity in pallial and subpallial tissues is associated with a reduction in the number of cells migrating out of GE explants. The uPAR knockout mouse provides a unique opportunity to study the effects of interneuron disruption in vivo. uPAR ^−/− mice have reduced HGF/SF bioactivity in the GE during the period of interneuron development and a concomitant 50% reduction in the number of GABAergic interneurons seeding frontal and parietal regions of the cerebral cortex. Behaviorally, these mice display an increased susceptibility to seizures, heightened anxiety, and diminished social interaction. This article discusses the commonalities between the functional defects seen in uPAR ^−/− mice and those of humans with developmental disorders, such as epilepsy, schizophrenia, and autism. It is suggested that disruption of GABAergic interneuron development may represent a common point of convergence underlying the etiologies of many of these developmental disorders.     

BDNF and JNK Signaling Modulate Cortical Interneuron and Perineuronal Net Development: Implications for Schizophrenia-Linked 16p11.2 Duplication Syndrome

Schizophrenia (SZ) is a neurodevelopmental disorder caused by the interaction of genetic and environmental risk factors. One of the strongest genetic risk variants is duplication (DUP) of chr.16p11.2. SZ is characterized by cortical gamma-amino-butyric acid (GABA)ergic interneuron dysfunction and disruption to surrounding extracellular matrix structures, perineuronal nets (PNNs). Developmental maturation of GABAergic interneurons, and also the resulting closure of the critical period of cortical plasticity, is regulated by brain-derived neurotrophic factor (BDNF), although the mechanisms involved are unknown. Here, we show that BDNF promotes GABAergic interneuron and PNN maturation through JNK signaling. In mice reproducing the 16p11.2 DUP, where the JNK upstream activator Taok2 is overexpressed, we find that JNK is overactive and there are developmental abnormalities in PNNs, which persist into adulthood. Prefrontal cortex parvalbumin (PVB) expression is reduced, while PNN intensity is increased. Additionally, we report a unique role for TAOK2 signaling in the regulation of PVB interneurons. Our work implicates TAOK2-JNK signaling in cortical interneuron and PNN development, and in the responses to BDNF. It also demonstrates that over-activation of this pathway in conditions associated with SZ risk causes long-lasting disruption in cortical interneurons.     

Terminal field and firing selectivity of cholecystokinin-expressing interneurons in the hippocampal CA3 area

Hippocampal oscillations reflect coordinated neuronal activity on many timescales. Distinct types of GABAergic interneuron participate in the coordination of pyramidal cells over different oscillatory cycle phases. In the CA3 area, which generates sharp waves and gamma oscillations, the contribution of identified GABAergic neurons remains to be defined. We have examined the firing of a family of cholecystokinin-expressing interneurons during network oscillations in urethane-anesthetized rats and compared them with firing of CA3 pyramidal cells. The position of the terminals of individual visualized interneurons was highly diverse, selective, and often spatially coaligned with either the entorhinal or the associational inputs to area CA3. The spike timing in relation to theta and gamma oscillations and sharp waves was correlated with the innervated pyramidal cell domain. Basket and dendritic-layer-innervating interneurons receive entorhinal and associational inputs and preferentially fire on the ascending theta phase, when pyramidal cell assemblies emerge. Perforant-path-associated cells, driven by recurrent collaterals of pyramidal cells fire on theta troughs, when established pyramidal cell assemblies are most active. In the CA3 area, slow and fast gamma oscillations occurred on opposite theta oscillation phases. Perforant-path-associated and some COUP-TFII-positive interneurons are strongly coupled to both fast and slow gamma oscillations, but basket and dendritic-layer-innervating cells are weakly coupled to fast gamma oscillations only. During sharp waves, different interneuron types are activated, inhibited, or remain unaffected. We suggest that specialization in pyramidal cell domain and glutamatergic input-specific operations, reflected in the position of GABAergic terminals, is the evolutionary drive underlying the diversity of cholecystokinin-expressing interneurons.     

Novel fast adapting interneurons mediate cholinergic‐induced fast GABAA inhibitory postsynaptic currents in striatal spiny neurons

Previous work suggests that neostriatal cholinergic interneurons control the activity of several classes of GABAergic interneurons through fast nicotinic receptor‐mediated synaptic inputs. Although indirect evidence has suggested the existence of several classes of interneurons controlled by this mechanism, only one such cell type, the neuropeptide‐Y‐expressing neurogliaform neuron, has been identified to date. Here we tested the hypothesis that in addition to the neurogliaform neurons that elicit slow GABAergic inhibitory responses, another interneuron type exists in the striatum that receives strong nicotinic cholinergic input and elicits conventional fast GABAergic synaptic responses in projection neurons. We obtained in vitro slice recordings from double transgenic mice in which Channelrhodopsin‐2 was natively expressed in cholinergic neurons and a population of serotonin receptor‐3a‐Cre‐expressing GABAergic interneurons were visualized with tdTomato. We show that among the targeted GABAergic interneurons a novel type of interneuron, termed the fast‐adapting interneuron, can be identified that is distinct from previously known interneurons based on immunocytochemical and electrophysiological criteria. We show using optogenetic activation of cholinergic inputs that fast‐adapting interneurons receive a powerful supra‐threshold nicotinic cholinergic input in vitro. Moreover, fast adapting neurons are densely connected to projection neurons and elicit fast, GABA_A receptor‐mediated inhibitory postsynaptic current responses. The nicotinic receptor‐mediated activation of fast‐adapting interneurons may constitute an important mechanism through which cholinergic interneurons control the activity of projection neurons and perhaps the plasticity of their synaptic inputs when animals encounter reinforcing or otherwise salient stimuli.     

匹罗卡品致癎大鼠海马γ-氨基丁酸能中间神经元生长抑素和微清蛋白mRNA表达研究

目的观察匹罗卡品致癎大鼠海马γ-氨基丁酸能中间神经元生长抑素（SS）mRNA和微清蛋白（PV）mRNA表达水平变化,拟从基因水平探讨其表达阳性叮一氨基丁酸能中间神经元在颞叶癫癎发生发展中的作用。方法建立匹罗卡品致癎大鼠模型,采用原位杂交法检测各观察时间点海马SSmRNA和PVmRNA表达阳性神经元数目。结果模型组大鼠海马各区吖．氨基丁酸能中间神经元SSmRNA表达水平均于出现癫癎持续状态后3d降低最为显著（均P=0．000）,随后逐渐升高;至发病后60d,海马CA3区SSmRNA表达水平高于对照组（t=1．021,P=0．005）,海马门区（t=3．211,P=0．009）和CA1区（t=1．902,JP=0．048）则仍低于对照组。模型组大鼠海马门区γ-氨基丁酸能中间神经元PVmRNA表达水平于出现癫癎持续状态后6h开始降低,至发病后60d降低最为显著（均P：0．000）;海马CA1区PVmRNA表达水平于发病后3d降低最为显著（均p=0．000）,随后逐渐升高但仍低于对照组（t=2．216,尸：0．048）;癫癎持续状态早期,海马CA3区PVmRNA表达水平无明显变化,至发病后7d逐渐升高且高于对照组（t=1．021,P=0．005）。结论γ-氨基丁酸能中间神经元SSmRNA和PVmRNA表达水平的下调可能在颞叶癫癎的发生中起重要作用,至慢性期γ-氨基丁酸能中间神经元SSmRNA和PVmRNA表达水平的恢复或上调可能与颞叶癫癎的发展或修复有关。γ-氨基丁酸能中间神经元数目的变化,部分是由于其标志物mRNA表达水平的调节所致,并非神经元数目变化的唯一因素。     

GABAergic and non-GABAergic spiking interneurons of local and intersegmental groups in the crayfish terminal abdominal ganglion.

In the first step toward identifying the neurotransmitter released from spiking interneurons of both local and intersegmental groups in the crayfish terminal abdominal ganglion, the authors examined whether spiking local interneurons and ascending intersegmental interneurons contain the transmitter gamma-aminobutyric acid (GABA). In this paper, 17 identified ascending interneurons and three spiking local interneurons were stained by intracellular injection of Lucifer yellow and subsequently treated for immunocytochemical staining against GABA. Double-labeling experiments revealed that six identified ascending interneurons are GABAergic, but no spiking local interneurons show GABA-like immunoreactivity. Four ascending interneurons with GABA-like immunoreactivity (reciprocal closing ascending neuron 5 [RC-5], reciprocal opening ascending neuron 6 [RO-6], variable-effect ascending interneuron 1 [VE-1], and no-effect ascending interneuron 4[NE-4]) had cell bodies that formed a cluster on the ventral surface of the rostral edge of the ganglion, whereas two GABAergic interneurons (coinhibiting ascending interneuron 2 [CI-2] and NE-2) had cell bodies in a caudal region around the cell body of the seventh flexor inhibitor (FI) motor neuron. Another four rostral interneurons (RC-2, RC-3, RC-4, and NE-3) and seven caudal interneurons (CI-3, RC-7, RO-1, RO-2, RO-3, RO-4, and NE-1) had no GABA-like immunoreactivity. Because VE-1 is known to make direct inhibitory connections with other ascending interneurons, whereas RC-3 and RO-1 are known to make direct excitatory connections, the immunocytochemical results from this study are consistent with previous physiological studies. Although many spiking local interneurons (including spiking local interneuron 1 of the anterior group [sp-ant1]) made direct inhibitory connections with nonspiking local interneurons, three spiking local interneurons (sp-ant1, spiking local interneuron 6 of the medial group [sp-med6], and spiking interneuron 5 of the posterior group [sp-post]) do not show GABA-like immunoreactivity. These results suggest that the inhibitory transmitter released from spiking local interneurons is not GABA but that another substance mediates the inhibitory action of these interneurons. J. Comp. Neurol. 410:677-688.     

Histological characterization of interneurons in Alzheimer's disease reveals a loss of somatostatin interneurons in the temporal cortex

Neuronal dysfunction and synaptic loss are major hallmarks of Alzheimer's disease (AD) which correlate with symptom severity. Impairment of the γ-aminobutyric acid (GABA)ergic inhibitory interneurons, which form around 20% of the total neuronal network, may be an early event contributing to neuronal circuit dysfunction in neurodegenerative diseases. This study examined the expression of two of the main classes of inhibitory interneurons, parvalbumin (PV) and somatostatin (SST) interneurons in the temporal cortex and hippocampus of AD and control cases, using immunohistochemistry. We report a significant regional variation in the number of PV and SST interneurons with a higher number identified per mm² in the temporal cortex compared to the hippocampus. Fewer SST interneurons, but not PV interneurons, were identified per mm² in the temporal cortex of AD cases compared to control subjects. Our results support regional neuroanatomical effects on selective interneuron classes in AD, and suggest that impairment of the interneuronal circuit may contribute to neuronal dysfunction and cognitive decline in AD.     

Immunocytochemical heterogeneity of somatostatin‐expressing GABAergic interneurons in layers II and III of the mouse cingulate cortex: A combined immunofluorescence/design‐based stereologic study

Many neurological diseases including major depression and schizophrenia manifest as dysfunction of the GABAergic system within the cingulate cortex. However, relatively little is known about the properties of GABAergic interneurons in the cingulate cortex. Therefore, we investigated the neurochemical properties of GABAergic interneurons in the cingulate cortex of FVB‐Tg(GadGFP)45704Swn/J mice expressing green fluorescent protein (GFP) in a subset of GABAergic interneurons (GFP‐expressing inhibitory interneurons [GINs]) by means of immunocytochemical and design‐based stereologic techniques. We found that GINs represent around 12% of all GABAergic interneurons in the cingulate cortex. In contrast to other neocortical areas, GINs were only found in cortical layers II and III. More than 98% of GINs coexpressed the neuropeptide somatostatin (SOM), but only 50% of all SOM + neurons were GINs. By analyzing the expression of calretinin (CR), calbindin (CB), parvalbumin, and various neuropeptides, we identified several distinct GIN subgroups. In particular, we observed coexpression of SOM with CR and CB. In addition, we found neuropeptide Y expression almost exclusively in those GINs that coexpressed SOM and CR. Thus, with respect to the expression of calcium‐binding proteins and neuropeptides, GINs are surprisingly heterogeneous in the mouse cingulate cortex, and the minority of GINs express only one marker protein or peptide. Furthermore, our observation of overlap between the SOM + and CR + interneuron population was in contrast to earlier findings of non‐overlapping SOM + and CR + interneuron populations in the human cortex. This might indicate that findings in mouse models of neuropsychiatric diseases may not be directly transferred to human patients. J. Comp. Neurol. 524:2281–2299, 2016. © 2015 Wiley Periodicals, Inc.     

Hepatocyte growth factor (HGF) modulates GABAergic inhibition and seizure susceptibility

Disrupted ontogeny of forebrain inhibitory interneurons leads to neurological disorders, including epilepsy. Adult mice lacking the urokinase plasminogen activator receptor (Plaur) have decreased numbers of neocortical GABAergic interneurons and spontaneous seizures, attributed to a reduction of hepatocyte growth factor/scatter factor (HGF/SF). We report that by increasing endogenous HGF/SF concentration in the postnatal Plaur null mouse brain maintains the interneuron populations in the adult, reverses the seizure behavior and stabilizes the spontaneous electroencephalogram activity. The perinatal intervention provides a pathway to reverse potential birth defects and ameliorate seizures in the adult.     

GABAergic-astrocyte signaling: A refinement of inhibitory brain networks

Interneurons play a critical role in precise control of network operation. Indeed, higher brain capabilities such as working memory, cognitive flexibility, attention, or social interaction rely on the action of GABAergic interneurons. Evidence from excitatory neurons and synapses has revealed astrocytes as integral elements of synaptic transmission. However, GABAergic interneurons can also engage astrocyte signaling; therefore, it is tempting to speculate about different scenarios where, based on particular interneuron cell type, GABAergic-astrocyte interplay would be involved in diverse outcomes of brain function. In this review, we will highlight current data supporting the existence of dynamic GABAergic-astrocyte communication and its impact on the inhibitory-regulated brain responses, bringing new perspectives on the ways astrocytes might contribute to efficient neuronal coding.     

GABAergic excitatory synapses and electrical coupling sustain prolonged discharges in the prey capture neural network of Clione limacina.

Afterdischarges represent a prominent characteristic of the neural network that controls prey capture reactions in the carnivorous mollusc Clione limacina. Their main functional implication is transformation of a brief sensory input from a prey into a lasting prey capture response. The present study, which focuses on the neuronal mechanisms of afterdischarges, demonstrates that a single pair of interneurons [cerebral A interneuron (Cr-Aint)] is responsible for afterdischarge generation in the network. Cr-Aint neurons are electrically coupled to all other neurons in the network and produce slow excitatory synaptic inputs to them. This excitatory transmission is found to be GABAergic, which is demonstrated by the use of GABA antagonists, uptake inhibitors, and double-labeling experiments showing that Cr-Aint neurons are GABA-immunoreactive. The Cr-Aint neurons organize three different pathways in the prey capture network, which provide positive feedback necessary for sustaining prolonged spike activity. The first pathway includes electrical coupling and slow chemical transmission from the Cr-Aint neurons to all other neurons in the network. The second feedback is based on excitatory reciprocal connections between contralateral interneurons. Recurrent excitation via the contralateral cell can sustain prolonged interneuron firing, which then drives the activity of all other cells in the network. The third positive feedback is represented by prominent afterdepolarizing potentials after individual spikes in the Cr-Aint neurons. Afterdepolarizations apparently represent recurrent GABAergic excitatory inputs. It is suggested here that these afterdepolarizing potentials are produced by GABAergic excitatory autapses.