Showing papers on "GABAergic published in 2021"

Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders

Abstract: Cognitive dysfunctions, including impaired attention, learning, memory, planning and problem solving, occur in depressive episodes, often persist during remission, predict relapse, worsen with recurrent episodes, and are not treated by current antidepressants or other medications. Cognitive symptoms are also present in other psychiatric disorders, are a hallmark of aging, and define several late-life disorders, including Alzheimer's disease. This pervasive occurrence suggests either a non-specific outcome of a diseased brain, or a shared underlying pathology contributing to this symptom dimension. Recent findings suggest a role for altered GABAergic inhibition in cognitive symptoms. Cellular, molecular and biochemical studies in human subjects report changes affecting the gamma-amino butyric acid (GABA) system, specifically somatostatin-expressing (SST+) GABAergic interneurons, across brain disorders and during aging. SST+ neurons gate excitatory input onto pyramidal neurons within cortical microcircuits. Experimentally reducing the function of these neurons affects excitatory signal-to-noise ratio, reduces synchronized cellular and neural activity, and leads to cognitive dysfunctions. Conversely, augmenting SST+ cell post-synaptic α5-GABA-A receptor activity has pro-cognitive efficacy in stress and aging models. Together, this suggests that reduced signaling of the SST+ neuron/α5-GABA-A receptor pathway contributes to cognitive dysfunctions, and that it represents a novel therapeutic target for remediating mood and cognitive symptoms in depression, other psychiatric disorders and during aging.

GABAergic signaling to astrocytes in the prefrontal cortex sustains goal-directed behaviors.

Abstract: GABA interneurons play a critical role in higher brain functions. Astrocytic glial cells interact with synapses throughout the whole brain and are recognized as regulatory elements of excitatory synaptic transmission. However, it is largely unknown how GABAergic interneurons and astrocytes interact and contribute to stable performance of complex behaviors. Here, we found that genetic ablation of GABAB receptors in medial prefrontal cortex astrocytes altered low-gamma oscillations and firing properties of cortical neurons, which affected goal-directed behaviors. Remarkably, working memory deficits were restored by optogenetic stimulation of astrocytes with melanopsin. Furthermore, melanopsin-activated astrocytes in wild-type mice enhanced the firing rate of cortical neurons and gamma oscillations, as well as improved cognition. Therefore, our work identifies astrocytes as a hub for controlling inhibition in cortical circuits, providing a novel pathway for the behaviorally relevant midrange time-scale regulation of cortical information processing and consistent goal-directed behaviors.

The role of GABAergic signalling in neurodevelopmental disorders.

Abstract: GABAergic inhibition shapes the connectivity, activity and plasticity of the brain. A series of exciting new discoveries provides compelling evidence that disruptions in a number of key facets of GABAergic inhibition have critical roles in the aetiology of neurodevelopmental disorders (NDDs). These facets include the generation, migration and survival of GABAergic neurons, the formation of GABAergic synapses and circuit connectivity, and the dynamic regulation of the efficacy of GABAergic signalling through neuronal chloride transporters. In this Review, we discuss recent work that elucidates the functions and dysfunctions of GABAergic signalling in health and disease, that uncovers the contribution of GABAergic neural circuit dysfunction to NDD aetiology and that leverages such mechanistic insights to advance precision medicine for the treatment of NDDs.

GABA Production by Human Intestinal Bacteroides spp.: Prevalence, Regulation, and Role in Acid Stress Tolerance.

Abstract: The high neuroactive potential of metabolites produced by gut microbes has gained traction over the last few years, with metagenomic-based studies suggesting an important role of microbiota-derived γ-aminobutyric acid (GABA) in modulating mental health. Emerging evidence has revealed the presence of the glutamate decarboxylase (GAD)-encoding gene, a key enzyme to produce GABA, in the prominent human intestinal genus Bacteroides. Here, we investigated GABA production by Bacteroides in culture and metabolic assays combined with comparative genomics and phylogenetics. A total of 961 Bacteroides genomes were analyzed in silico and 17 metabolically and genetically diverse human intestinal isolates representing 11 species were screened in vitro. Using the model organism Bacteroides thetaiotaomicron DSM 2079, we determined GABA production kinetics, its impact on milieu pH, and we assessed its role in mitigating acid-induced cellular damage. We showed that the GAD-system consists of at least four highly conserved genes encoding a GAD, a glutaminase, a glutamate/GABA antiporter, and a potassium channel. We demonstrated a high prevalence of the GAD-system among Bacteroides with 90% of all Bacteroides genomes (96% in human gut isolates only) harboring all genes of the GAD-system and 16 intestinal Bacteroides strains producing GABA in vitro (ranging from 0.09 to 60.84 mM). We identified glutamate and glutamine as precursors of GABA production, showed that the production is regulated by pH, and that the GAD-system acts as a protective mechanism against acid stress in Bacteroides, mitigating cell death and preserving metabolic activity. Our data also indicate that the GAD-system might represent the only amino acid-dependent acid tolerance system in Bacteroides. Altogether, our results suggest an important contribution of Bacteroides in the regulation of the GABAergic system in the human gut.

A new GABAergic somatostatin projection from the BNST onto accumbal parvalbumin neurons controls anxiety.

Abstract: The prevailing view is that parvalbumin (PV) interneurons play modulatory roles in emotional response through local medium spiny projection neurons (MSNs) Here, we show that PV activity within the nucleus accumbens shell (sNAc) is required for producing anxiety-like avoidance when mice are under anxiogenic situations Firing rates of sNAcPV neurons were negatively correlated to exploration time in open arms (threatening environment) In addition, sNAcPV neurons exhibited high excitability in a chronic stress mouse model, which generated excessive maladaptive avoidance behavior in an anxiogenic context We also discovered a novel GABAergic pathway from the anterior dorsal bed nuclei of stria terminalis (adBNST) to sNAcPV neurons Optogenetic activation of these afferent terminals in sNAc produced an anxiolytic effect via GABA transmission Next, we further demonstrated that chronic stressors attenuated the inhibitory synaptic transmission at adBNSTGABA → sNAcPV synapses, which in turn explains the hyperexcitability of sNAc PV neurons on stressed models Therefore, activation of these GABAergic afferents in sNAc rescued the excessive avoidance behavior related to an anxious state Finally, we identified that the majority GABAergic input neurons, which innervate sNAcPV cells, were expressing somatostatin (SOM), and also revealed that coordination between SOM- and PV- cells functioning in the BNST → NAc circuit has an inhibitory influence on anxiety-like responses Our findings provide a potentially neurobiological basis for therapeutic interventions in pathological anxiety

Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses.

Abstract: Major depressive disorder (MDD) is associated with alterations of GABAergic interneurons, notably somatostatin (Sst) as well as parvalbumin (Pvalb), in cortical brain areas. In addition, the antidepressant effects of rapid-acting drugs are thought to occur via inhibition of GABA interneurons. However, the impact of these interneuron subtypes in affective behaviors as well as in the effects of rapid-acting antidepressants remains to be determined. Here, we used a Cre-dependent DREADD-chemogenetic approach to determine if inhibition of GABA interneurons in the mPFC of male mice is sufficient to produce antidepressant actions, and conversely if activation of these interneurons blocks the rapid and sustained antidepressant effects of scopolamine, a nonselective acetylcholine muscarinic receptor antagonist. Chemogenetic inhibition of all GABA interneurons (Gad1+), as well as Sst+ and Pvalb+ subtypes in the mPFC produced dose and time-dependent antidepressant effects in the forced swim and novelty suppressed feeding tests, and increased synaptic plasticity. In contrast, stimulation of Gad1, Sst, or Pvalb interneurons in mPFC abolished the effects of scopolamine and prevented scopolamine induction of synaptic plasticity. The results demonstrate that transient inhibition of GABA interneurons promotes synaptic plasticity that underlies rapid antidepressant responses.

Ventral pallidal GABAergic neurons control wakefulness associated with motivation through the ventral tegmental pathway.

Abstract: The ventral pallidum (VP) regulates motivation, drug addiction, and several behaviors that rely on heightened arousal. However, the role and underlying neural circuits of the VP in the control of wakefulness remain poorly understood. In the present study, we sought to elucidate the specific role of VP GABAergic neurons in controlling sleep-wake behaviors in mice. Fiber photometry revealed that the population activity of VP GABAergic neurons was increased during physiological transitions from non-rapid eye movement (non-REM, NREM) sleep to either wakefulness or REM sleep. Moreover, chemogenetic and optogenetic manipulations were leveraged to investigate a potential causal role of VP GABAergic neurons in initiating and/or maintaining arousal. In vivo optogenetic stimulation of VP GABAergic neurons innervating the ventral tegmental area (VTA) strongly promoted arousal via disinhibition of VTA dopaminergic neurons. Functional in vitro mapping revealed that VP GABAergic neurons, in principle, inhibited VTA GABAergic neurons but also inhibited VTA dopaminergic neurons. In addition, optogenetic stimulation of terminals of VP GABAergic neurons revealed that they promoted arousal by innervating the lateral hypothalamus, but not the mediodorsal thalamus or lateral habenula. The increased wakefulness chemogenetically evoked by VP GABAergic neuronal activation was completely abolished by pretreatment with dopaminergic D1 and D2/D3 receptor antagonists. Furthermore, activation of VP GABAergic neurons increased exploration time in both the open-field and light-dark box tests but did not modulate depression-like behaviors or food intake. Finally, chemogenetic inhibition of VP GABAergic neurons decreased arousal. Taken together, our findings indicate that VP GABAergic neurons are essential for arousal related to motivation.

Subcellular sequencing of single neurons reveals the dendritic transcriptome of GABAergic interneurons

Abstract: Although mRNAs are localized in the processes of excitatory neurons, it is still unclear whether interneurons also localize a large population of mRNAs. In addition, the variability in the localized mRNA population within and between cell-types is unknown. Here we describe the unbiased transcriptomic characterization of the subcellular compartments of hundreds of single neurons. We separately profiled the dendritic and somatic transcriptomes of individual rat hippocampal neurons and investigated mRNA abundances in the soma and dendrites of single glutamatergic and GABAergic neurons. We found that, like their excitatory counterparts, interneurons contain a rich repertoire of ~4000 mRNAs. We observed more cell type-specific features among somatic transcriptomes than their associated dendritic transcriptomes. Finally, using cell-type specific metabolic labelling of isolated neurites, we demonstrated that the processes of Glutamatergic and, notably, GABAergic neurons were capable of local translation, suggesting mRNA localization and local translation is a general property of neurons.

Reciprocal control of obesity and anxiety-depressive disorder via a GABA and serotonin neural circuit

Abstract: The high comorbidity between obesity and mental disorders, such as depression and anxiety, often exacerbates metabolic and neurological symptoms significantly. However, neural mechanisms that underlie reciprocal control of feeding and mental states are largely elusive. Here we report that melanocortin 4 receptor (MC4R) neurons located in the dorsal bed nucleus of the stria terminus (dBNST) engage in the regulation of mentally associated weight gain by receiving GABAergic projections from hypothalamic AgRP neurons onto α5-containing GABAA receptors and serotonergic afferents onto 5-HT3 receptors. Chronic treatment with a high-fat diet (HFD) significantly blunts the hyperexcitability of AgRP neurons in response to not only hunger but also anxiety and depression-like stimuli. Such HFD-mediated desensitization reduces GABAergic outputs from AgRP neurons to downstream MC4RdBNST neurons, resulting in severe mental dysregulation. Genetic enhancement of the GABAAR-α5 or suppression of the 5-HT3R within the MC4RdBNST neurons not only abolishes HFD-induced anxiety and depression but also robustly reduces body weight by suppression of food intake. To gain further translational insights, we revealed that combined treatment of zonisamide (enhancing the GABAAR-α5 signaling) and granisetron (a selective 5-HT3R antagonist) alleviates mental dysfunction and yields a robust reversal of diet-induced obesity by reducing total calorie intake and altering food preference towards a healthy low-fat diet. Our results unveil a neural mechanism for reciprocal control of appetite and mental states, which culminates in a novel zonisamide-granisetron cocktail therapy for potential tackling the psychosis-obesity comorbidity.

Top-down control of hippocampal signal-to-noise by prefrontal long-range inhibition

Abstract: Summary The prefrontal cortex (PFC) is postulated to exert ‘top-down control’ by modulating information processing throughout the brain to promote specific actions based on current goals. However, the pathways mediating top-down control remain poorly understood. In particular, knowledge about direct prefrontal connections that might facilitate top-down prefrontal control of information processing in the hippocampus remains sparse. Here we describe novel monosynaptic long-range GABAergic projections from PFC to hippocampus. These preferentially inhibit vasoactive intestinal polypeptide expressing interneurons, which are known to disinhibit hippocampal microcircuits. Indeed, stimulating prefrontal–hippocampal GABAergic projections increases hippocampal feedforward inhibition and reduces hippocampal activity in vivo. The net effect of these actions is to specifically enhance the signal-to-noise ratio for hippocampal representations of objects. Correspondingly, stimulation of PFC-to-hippocampus GABAergic projections promotes object exploration. Together, these results elucidate a novel top-down pathway in which long-range GABAergic projections target disinhibitory microcircuits, thereby enhancing signals and network dynamics underlying exploratory behavior.

Ventral tegmental area GABAergic inhibition of cholinergic interneurons in the ventral nucleus accumbens shell promotes reward reinforcement

Abstract: The long-range GABAergic input from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) is relatively understudied, and therefore its role in reward processing has remained unknown. In the present study, we show, in both male and female mice, that long-range GABAergic projections from the VTA to the ventral NAc shell, but not to the dorsal NAc shell or NAc core, are engaged in reward and reinforcement behavior. We show that this GABAergic projection exclusively synapses on to cholinergic interneurons (CINs) in the ventral NAc shell, thereby serving a specialized function in modulating reinforced reward behavior through the inhibition of ventral NAc shell CINs. These findings highlight the diversity in the structural and functional topography of VTA GABAergic projections, and their neuromodulatory interactions across the dorsoventral gradient of the NAc shell. They also further our understanding of neuronal circuits that are directly implicated in neuropsychiatric conditions such as depression and addiction.

Ventral tegmental area GABA neurons mediate stress-induced blunted reward-seeking in mice.

Abstract: Decreased pleasure-seeking (anhedonia) forms a core symptom of depression. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. We recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) that predicts the degree of subsequent blunted reward-seeking. Surprisingly, while previous studies on blunted reward-seeking focused on dopamine (DA) transmission from the ventral tegmental area (VTA) to the NAc, we found that VTA GABA, but not DA, neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz reproduces both oscillations and blunted reward-seeking. Finally, we find that stress disrupts VTA GABA, but not DA, neural encoding of reward anticipation. Thus, stress elicits VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking. Acute stress transiently disrupts reward-seeking behaviour and repeated stress exposure produces lasting anhedonia-like behaviour in rodents. Here, the authors show that stress triggers GABAergic activity in the ventral tegmental area which blunts reward-seeking behaviour in mice.

Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4

Abstract: The human 16p11.2 gene locus is a hot spot for copy number variations, which predispose carriers to a range of neuropsychiatric phenotypes. Microduplications of 16p11.2 are associated with autism spectrum disorder (ASD), intellectual disability (ID), and schizophrenia (SZ). Despite the debilitating nature of 16p11.2 duplications, the underlying molecular mechanisms remain poorly understood. Here we performed a comprehensive behavioral characterization of 16p11.2 duplication mice (16p11.2dp/+) and identified social and cognitive deficits reminiscent of ASD and ID phenotypes. 16p11.2dp/+ mice did not exhibit the SZ-related sensorimotor gating deficits, psychostimulant-induced hypersensitivity, or motor impairment. Electrophysiological recordings of 16p11.2dp/+ mice found deficient GABAergic synaptic transmission and elevated neuronal excitability in the prefrontal cortex (PFC), a brain region critical for social and cognitive functions. RNA-sequencing identified genome-wide transcriptional aberrance in the PFC of 16p11.2dp/+ mice, including downregulation of the GABA synapse regulator Npas4. Restoring Npas4 expression in PFC of 16p11.2dp/+ mice ameliorated the social and cognitive deficits and reversed GABAergic synaptic impairment and neuronal hyperexcitability. These findings suggest that prefrontal cortical GABAergic synaptic circuitry and Npas4 are strongly implicated in 16p11.2 duplication pathology, and may represent potential targets for therapeutic intervention in ASD.

Convergence of adenosine and GABA signaling for synapse stabilization during development.

Abstract: During development, neural circuit formation requires the stabilization of active γ-aminobutyric acid–mediated (GABAergic) synapses and the elimination of inactive ones. Here, we demonstrate that, although the activation of postsynaptic GABA type A receptors (GABAARs) and adenosine A2A receptors (A2ARs) stabilizes GABAergic synapses, only A2AR activation is sufficient. Both GABAAR- and A2AR-dependent signaling pathways act synergistically to produce adenosine 3′,5′-monophosphate through the recruitment of the calcium–calmodulin–adenylyl cyclase pathway. Protein kinase A, thus activated, phosphorylates gephyrin on serine residue 303, which is required for GABAAR stabilization. Finally, the stabilization of pre- and postsynaptic GABAergic elements involves the interaction between gephyrin and the synaptogenic membrane protein Slitrk3. We propose that A2ARs act as detectors of active GABAergic synapses releasing GABA, adenosine triphosphate, and adenosine to regulate their fate toward stabilization or elimination.

Cadherin-13 is a critical regulator of GABAergic modulation in human stem-cell-derived neuronal networks

Abstract: Activity in the healthy brain relies on a concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of studies imply that disruption of this E/I balance is a commonality in many brain disorders; however, obtaining mechanistic insight into these disruptions, with translational value for the patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) has been associated with autism and attention-deficit/hyperactivity disorder. CDH13 localizes at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from human-induced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and MEF2C (PV-precursor marker protein) expressing GABAergic neurons (iGABA) in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13 deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-β1 and Integrin-β3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type-specific contribution of disease genes to the E/I balance.

Dysregulation of REV-ERBα impairs GABAergic function and promotes epileptic seizures in preclinical models.

Abstract: To design potentially more effective therapies, we need to further understand the mechanisms underlying epilepsy. Here, we uncover the role of Rev-erbα in circadian regulation of epileptic seizures. We first show up-regulation of REV-ERBα/Rev-erbα in brain tissues from patients with epilepsy and a mouse model. Ablation or pharmacological modulation of Rev-erbα in mice decreases the susceptibility to acute and chronic seizures, and abolishes diurnal rhythmicity in seizure severity, whereas activation of Rev-erbα increases the animal susceptibility. Rev-erbα ablation or antagonism also leads to prolonged spontaneous inhibitory postsynaptic currents and elevated frequency in the mouse hippocampus, indicating enhanced GABAergic signaling. We also identify the transporters Slc6a1 and Slc6a11 as regulators of Rev-erbα-mediated clearance of GABA. Mechanistically, Rev-erbα promotes the expressions of Slc6a1 and Slc6a11 through transcriptional repression of E4bp4. Our findings propose Rev-erbα as a regulator of synaptic function at the crosstalk between pathways regulating the circadian clock and epilepsy.

Enhancing GABAergic signaling ameliorates aberrant gamma oscillations of olfactory bulb in AD mouse models

Abstract: Before the deposition of amyloid-beta plaques and the onset of learning memory deficits, patients with Alzheimer’s disease (AD) experience olfactory dysfunction, typified by a reduced ability to detect, discriminate, and identify odors. Rodent models of AD, such as the Tg2576 and APP/PS1 mice, also display impaired olfaction, accompanied by aberrant in vivo or in vitro gamma rhythms in the olfactory pathway. However, the mechanistic relationships between the electrophysiological, biochemical and behavioral phenomena remain unclear. To address the above issues in AD models, we conducted in vivo measurement of local field potential (LFP) with a combination of in vitro electro-olfactogram (EOG), whole-cell patch and field recordings to evaluate oscillatory and synaptic function and pharmacological regulation in the olfactory pathway, particularly in the olfactory bulb (OB). Levels of protein involved in excitation and inhibition of the OB were investigated by western blotting and fluorescence staining, while behavioral studies assessed olfaction and memory function. LFP measurements demonstrated an increase in gamma oscillations in the OB accompanied by altered olfactory behavior in both APP/PS1 and 3xTg mice at 3–5 months old, i.e. an age before the onset of plaque formation. Fewer olfactory sensory neurons (OSNs) and a reduced EOG contributed to a decrease in the excitatory responses of M/T cells, suggesting a decreased ability of M/T cells to trigger interneuron GABA release indicated by altered paired-pulse ratio (PPR), a presynaptic parameter. Postsynaptically, there was a compensatory increase in levels of GABAAR α1 and β3 subunits and subsequent higher amplitude of inhibitory responses. Strikingly, the GABA uptake inhibitor tiagabine (TGB) ameliorated abnormal gamma oscillations and levels of GABAAR subunits, suggesting a potential therapeutic strategy for early AD symptoms. These findings reveal increased gamma oscillations in the OB as a core indicator prior to onset of AD and uncover mechanisms underlying aberrant gamma activity in the OB. This study suggests that the concomitant dysfunction of both olfactory behavior and gamma oscillations have important implications for early AD diagnosis: in particular, awareness of aberrant GABAergic signaling mechanisms might both aid diagnosis and suggest therapeutic strategies for olfactory damage in AD.

Ventromedial prefrontal cortex/anterior cingulate cortex Glx, glutamate, and GABA levels in medication-free major depressive disorder

Abstract: Glutamate (Glu) and gamma-aminobutyric acid (GABA) are implicated in the pathophysiology of major depressive disorder (MDD). GABA levels or GABAergic interneuron numbers are generally low in MDD, potentially disinhibiting Glu release. It is unclear whether Glu release or turnover is increased in depression. Conversely, a meta-analysis of prefrontal proton magnetic resonance spectroscopy (1H MRS) studies in MDD finds low Glx (combination of glutamate and glutamine) in medicated MDD. We hypothesize that elevated Glx or Glu may be a marker of more severe, untreated MDD. We examined ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC) Glx and glutamate levels using 1H MRS in 34 medication-free, symptomatic, chronically ill MDD patients and 32 healthy volunteers, and GABA levels in a subsample. Elevated Glx and Glu were observed in MDD compared with healthy volunteers, with the highest levels seen in males with MDD. vmPFC/ACC GABA was low in MDD. Higher Glx levels correlated with more severe depression and lower GABA. MDD severity and diagnosis were both linked to higher Glx in vmPFC/ACC. Low GABA in a subset of these patients is consistent with our hypothesized model of low GABA leading to glutamate disinhibition in MDD. This finding and model are consistent with our previously reported findings that the NMDAR-antagonist antidepressant effect is proportional to the reduction of vmPFC/ACC Glx or Glu levels.

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer's Disease.

Abstract: The physiological balance between excitation and inhibition in the brain is significantly affected in Alzheimer's disease (AD). Several neuroactive compounds and their signaling pathways through various types of receptors are crucial in brain homeostasis, among them glutamate and γ-aminobutyric acid (GABA). Activation of microglial receptors regulates the immunological response of these cells, which in AD could be neuroprotective or neurotoxic. The novel research approaches revealed the complexity of microglial function, including the interplay with other cells during neuroinflammation and in the AD brain. The purpose of this review is to describe the role of several proteins and multiple receptors on microglia and neurons, and their involvement in a communication network between cells that could lead to different metabolic loops and cell death/survival. Our review is focused on the role of glutamatergic, GABAergic signaling in microglia-neuronal cross-talk in AD and neuroinflammation. Moreover, the significance of AD-related neurotoxic proteins in glutamate/GABA-mediated dialogue between microglia and neurons was analyzed in search of novel targets in neuroprotection, and advanced pharmacological approaches.

Activity-dependent regulome of human GABAergic neurons reveals new patterns of gene regulation and neurological disease heritability

Abstract: Neuronal activity-dependent gene expression is essential for brain development. Although transcriptional and epigenetic effects of neuronal activity have been explored in mice, such an investigation is lacking in humans. Because alterations in GABAergic neuronal circuits are implicated in neurological disorders, we conducted a comprehensive activity-dependent transcriptional and epigenetic profiling of human induced pluripotent stem cell-derived GABAergic neurons similar to those of the early developing striatum. We identified genes whose expression is inducible after membrane depolarization, some of which have specifically evolved in primates and/or are associated with neurological diseases, including schizophrenia and autism spectrum disorder (ASD). We define the genome-wide profile of human neuronal activity-dependent enhancers, promoters and the transcription factors CREB and CRTC1. We found significant heritability enrichment for ASD in the inducible promoters. Our results suggest that sequence variation within activity-inducible promoters of developing human forebrain GABAergic neurons contributes to ASD risk. Boulting et al. profile activity-dependent gene expression and regulatory elements in human induced pluripotent stem cell-derived GABAergic neurons and uncover a possible role for calcium-responsive gene promoters of these neurons in autism risk.

Gene regulatory networks controlling differentiation, survival, and diversification of hypothalamic Lhx6-expressing GABAergic neurons.

Abstract: GABAergic neurons of the hypothalamus regulate many innate behaviors, but little is known about the mechanisms that control their development. We previously identified hypothalamic neurons that express the LIM homeodomain transcription factor Lhx6, a master regulator of cortical interneuron development, as sleep-promoting. In contrast to telencephalic interneurons, hypothalamic Lhx6 neurons do not undergo long-distance tangential migration and do not express cortical interneuronal markers such as Pvalb. Here, we show that Lhx6 is necessary for the survival of hypothalamic neurons. Dlx1/2, Nkx2-2, and Nkx2-1 are each required for specification of spatially distinct subsets of hypothalamic Lhx6 neurons, and that Nkx2-2+/Lhx6+ neurons of the zona incerta are responsive to sleep pressure. We further identify multiple neuropeptides that are enriched in spatially segregated subsets of hypothalamic Lhx6 neurons, and that are distinct from those seen in cortical neurons. These findings identify common and divergent molecular mechanisms by which Lhx6 controls the development of GABAergic neurons in the hypothalamus.

Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes.

Abstract: Accumulating evidence supports immune involvement in the pathogenesis of schizophrenia, a severe psychiatric disorder. In particular, high expression variants of C4, a gene of the innate immune complement system, were shown to confer susceptibility to schizophrenia. However, how elevated C4 expression may impact brain circuits remains largely unknown. We used in utero electroporation to overexpress C4 in the mouse prefrontal cortex. We found reduced glutamatergic input to pyramidal cells of juvenile and adult, but not of newborn C4-overexpressing (C4-OE) mice, together with decreased spine density, which mirrors spine loss observed in the schizophrenic cortex. Using time-lapse two-photon imaging in vivo, we observed that these deficits were associated with decreased dendritic spine gain and elimination in juvenile C4-OE mice, which may reflect poor formation and/or stabilization of immature spines. In juvenile and adult C4-OE mice, we found evidence for NMDA receptor hypofunction, another schizophrenia-associated phenotype, and synaptic accumulation of calcium-permeable AMPA receptors. Alterations in cortical GABAergic networks have been repeatedly associated with schizophrenia. We found that functional GABAergic transmission was reduced in C4-OE mice, in line with diminished GABA release probability from parvalbumin interneurons, lower GAD67 expression, and decreased intrinsic excitability in parvalbumin interneurons. These cellular abnormalities were associated with working memory impairment. Our results substantiate the causal relationship between an immunogenetic risk factor and several distinct cortical endophenotypes of schizophrenia and shed light on the underlying cellular mechanisms.