Dysfunction Of GABAergic Neurons Research Articles

Dysfunction of the Hippocampal-Lateral Septal Circuit Impairs Risk Assessment in Epileptic Mice.

Temporal lobe epilepsy, a chronic disease of the brain characterized by degeneration of the hippocampus, has impaired risk assessment. Risk assessment is vital for survival in complex environments with potential threats. However, the underlying mechanisms remain largely unknown. The intricate balance of gene regulation and expression across different brain regions is related to the structure and function of specific neuron subtypes. In particular, excitation/inhibition imbalance caused by hyperexcitability of glutamatergic neurons and/or dysfunction of GABAergic neurons, have been implicated in epilepsy. First, we estimated the risk assessment (RA) by evaluating the behavior of mice in the center of the elevated plus maze, and found that the kainic acid-induced temporal lobe epilepsy mice were specifically impaired their RA. This experiment evaluated approach-RA, with a forthcoming approach to the open arm, and avoid-RA, with forthcoming avoidance of the open arm. Next, results from free-moving electrophysiological recordings showed that in the hippocampus, ∼7% of putative glutamatergic neurons and ∼15% of putative GABAergic neurons were preferentially responsive to either approach-risk assessment or avoid-risk assessment, respectively. In addition, ∼12% and ∼8% of dorsal lateral septum GABAergic neurons were preferentially responsive to approach-risk assessment and avoid-risk assessment, respectively. Notably, during the impaired approach-risk assessment, the favorably activated dorsal dentate gyrus and CA3 glutamatergic neurons increased (∼9%) and dorsal dentate gyrus and CA3 GABAergic neurons decreased (∼7%) in the temporal lobe epilepsy mice. Then, we used RNA sequencing and immunohistochemical staining to investigate which subtype of GABAergic neuron loss may contribute to excitation/inhibition imbalance. The results show that temporal lobe epilepsy mice exhibit significant neuronal loss and reorganization of neural networks. In particular, the dorsal dentate gyrus and CA3 somatostatin-positive neurons and dorsal lateral septum cholecystokinin-positive neurons are selectively vulnerable to damage after temporal lobe epilepsy. Optogenetic activation of the hippocampal glutamatergic neurons or chemogenetic inhibition of the hippocampal somatostatin neurons directly disrupts RA, suggesting that an excitation/inhibition imbalance in the dHPC dorsal lateral septum circuit results in the impairment of RA behavior. Taken together, this study provides insight into epilepsy and its comorbidity at different levels, including molecular, cell, neural circuit, and behavior, which are expected to decrease injury and premature mortality in patients with epilepsy.

Diabetic encephalopathy causes the imbalance of neural activities between hippocampal glutamatergic neurons and GABAergic neurons in mice

Diabetic encephalopathy is a severe diabetes-related complication in the central nervous system (CNS) that is characterized by the impairment of neurochemical and structural changes leading to cognitive dysfunction. Its cellular and molecular mechanisms are still unclear and clinical approaches are still lacking of promising therapies. In this study, we have investigated the changes of different hippocampal neurons during diabetic encephalopathy in mouse models of diabetes by simultaneously analyzing the activities and synaptic transmission of glutamatergic neurons and GABAergic neurons in brain slices. Compared with the data from a group of control, diabetic encephalopathy permanently impairs the excitability of GABAergic neurons and synaptic transmission mediated by γ-aminobutyric acid (GABA). However, glutamatergic neurons appear to be more excited. Our findings highlight the critical role of the dysfunction of GABAergic neurons and glutamatergic neurons during diabetic encephalopathy in hippocampus to neural impairment as well as a strategy to prevent the function of progress of diabetic encephalopathy by protecting central neurons.

Pathology of nNOS-Expressing GABAergic Neurons in Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia that is often accompanied by mood and emotional disturbances and seizures. There is growing body of evidence that neurons expressing γ-aminobutyric acid (GABA) play an important role in regulation of cognition, mood, and emotion as well as seizure susceptibility, but participation of GABAergic neuronal pathology in Alzheimer’s disease (AD) is not understood well at present. Here, we report that transgenic mice expressing human amyloid precursor protein Swedish–Dutch–Iowa mutant (APPSweDI) exhibit early loss of neurons expressing GAD67, a GABA-synthesizing enzyme, in advance of the loss of pyramidal neurons in hippocampal CA1 region. The loss of GAD67+ neurons in APPSweDI mice accompanied with decreased spatial cognition as well as increased anxiety-like behaviors and kainic acid-induced seizure susceptibility at early phase. In the hippocampal CA1 region, GAD67+ neurons expressed high basal levels of neuronal nitric oxide synthase (nNOS) and nitrosative stress (nitrotyrosine). Similarly, GAD67+ neurons in primary cortical and hippocampal neuron cultures also expressed high basal levels of nNOS and degenerated in response to lower Aβ concentrations due to their high basal levels of nitrosative stress. Given the role of GABAergic neurons in cognitive and neuropsychiatric functions, this study reports the role of nNOS-mediated nitrosative stress in dysfunction of GABAergic neurons and its potential participation in early development of cognitive and neuropsychiatric symptoms in AD.

Dysfunction of GABAergic neurons in the parafacial zone mediates sleep disturbances in a streptozotocin-induced rat model of sporadic Alzheimer's disease.

Sleep disturbances are prevalent among patients with Alzheimer's disease (AD) and often precede the onset and progression of dementia. However, there are no reliable animal models for investigating sleep disturbances in patients with sporadic AD (sAD), which accounts for more than 90% of all AD cases. In the present study, we characterize the sleep/wake cycles and explore a potential mechanism underlying sleep disturbance in a rat model of sAD induced via intracerebroventricular (icv) injection of streptozotocin (STZ). STZ-icv rats exhibited progressive decreases in slow wave sleep (SWS) during the light phase and throughout the light/dark cycle beginning from 7days after STZ-icv. Additionally, increased wakefulness and decreased rapid-eye-movement (REM) and non-REM (NREM) sleep were observed from 14days after STZ-icv. Beginning on day 7, STZ-icv rats exhibited significant decreases in delta (0.5-4.0Hz) power accompanied by increased power in the beta (12-30Hz) and low gamma bands (30-50Hz) during NREM sleep, resembling deficits in sleep quality observed in patients with AD. Immunohistochemical staining revealed a significant reduction in the ratio of c-Fos-positive GABAergic neurons in the parafacial zone (PZ) beginning from day 7 after STZ-icv. These results suggest that the STZ-icv rat model is useful for evaluating sleep disturbances associated with AD, and implicate the dysregulation of GABAergic neuronal activity in the PZ is associated with sleep disturbance induced by STZ.

Ischemia deteriorates spike encoding at cortical GABAergic neurons and cerebellar Purkinje cells by increasing the intracellular Ca2.

GABAergic neurons play a critical role in the central nervous system, such as well-organized behaviors. The ischemic cell death is presumably initiated by neuronal excitotoxicity resulted from the dysfunction of GABAergic neurons. It is not clear how ischemia influences different types of GABAergic neurons and whether intracellular Ca2+ plays a key role in the ischemic excitotoxicity. We have investigated this issue at cortical GABAergic neurons and cerebellar Purkinje cells by whole-cell recording in mouse brain slices, and the roles of intracellular Ca2+ are examined by BABTA infusion. Compare with the data from a group of control, ischemia causes by lowering purfusion rate lowers spike encoding at cortical GABAergic neurons and enhances encoding ability at cerebellar Purkinje cells. These differential effects of ischemia on spike encoding are mechanistically associated with the changes in the refractory periods and threshold potentials of sequential spikes. These ischemia-induced dysfunction of spike encoding at two types of GABAergic cells are prevented by BABTA infusion. Therefore, the ischemia destabilizes the spike encoding of GABAergic cells via raising intracellular Ca2+. Our findings indicate that ischemia preferentially causes the dysfunction of spike encoding at GABAergic neurons by the up-regulation of intracellular Ca2+ level, which leads to neuronal excitotoxicity.

An impairment of cortical GABAergic neurons is involved in alkalosis-induced brain dysfunctions

Acid–base imbalance leads to pathological cognition and behaviors in the clinical practices. In the comparison with acidosis, the cellular mechanisms underlying alkalosis-induced brain dysfunction remain unclear. By using electrophysiological approach, we investigated the influences of high extracellular pH environment on cortical GABAergic neurons in terms of their responsiveness to synaptic inputs and their ability to produce action potentials. Artificial cerebral spinal fluid in high pH impairs excitatory synaptic transmission and spike initiation in cortical GABAergic neurons. The alkalosis-induced dysfunction of GABAergic neurons is associated with the decrease of receptor responsiveness and the increases of spike refractory periods and threshold potentials. Our studies reveal that alkalosis impairs cortical GABAergic neurons and subsequently deteriorate brain functions. The molecular targets for alkalosis action include glutamate receptor-channels and voltage-gated sodium channels on GABAergic neurons.

Identification of Arx targets unveils new candidates for controlling cortical interneuron migration and differentiation

Mutations in the homeobox transcription factor ARX have been found to be responsible for a wide spectrum of disorders extending from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of intellectual disabilities without apparent brain abnormalities, but with associated features of dystonia and epilepsy. Arx expression is mainly restricted to populations of GABA-containing neurons. Studies of the effects of ARX loss of function, either in humans or mutant mice, revealed varying defects, suggesting multiple roles of this gene in brain patterning, neuronal proliferation and migration, cell maturation and differentiation, as well as axonal outgrowth and connectivity. However, to date, little is known about how Arx functions as a transcription factor or which genes it binds and regulates. Recently, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified approximately 1000 gene promoters bound by Arx in transfected neuroblastoma N2a cells and mouse embryonic brain. To narrow the analysis of Arx targets to those most likely to control cortical interneuron migration and/or differentiation, we compare here our data to previously published studies searching for genes enriched or down-regulated in cortical interneurons between E13.5 and E15.5. We thus identified 14 Arx-target genes enriched (Cxcr7, Meis1, Ppap2a, Slc 12a5, Ets2, Phlda1, Egr1, Igf1, Lmo3, Sema6, Lgi1, Alk, Tgfb3, and Napb) and 5 genes specifically down-regulated (Hmgn3, Lmo1, Ebf3, Rasgef1b, and Slit2) in cortical migrating neurons. In this review, we present these genes and discuss how their possible regulation by Arx may lead to the dysfunction of GABAergic neurons, resulting in mental retardation and epilepsy.

Dysfunction of GABAergic neurons in the Engrailed 2 mouse model of autism

Dysfunction of GABAergic neurons in the Engrailed 2 mouse model of autism

Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes

SummaryMutations in the X-linked MECP2, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome (RTT) and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia, and encephalopathy with early lethality. RTT is characterized by apparently normal early development followed by regression, motor abnormalities, seizures, and features of autism, especially stereotyped behaviors. The mechanisms mediating these striking features are poorly understood. Here we show that mice lacking Mecp2 from γ-amino-butyric-acid-(GABA)-ergic neurons recapitulate numerous RTT and autistic features, including repetitive behaviors. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of RTT. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size consistent with presynaptic reduction in glutamic acid decarboxylase-1 and -2 levels and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal GABAergic neuronal function and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.

Neuroanatomical distribution of ARX in brain and its localisation in GABAergic neurons

Recent human genetics approaches identified the Aristaless-related homeobox ( ARX) gene as the causative gene in X-linked infantile spasms, Partington syndrome, and non-syndromic mental retardation as well as in forms of lissencephaly with abnormal genitalia. The ARX predicted protein belongs to a large family of homeoproteins and is characterised by a C-terminal Aristaless domain and an octapeptide domain near the N-terminus. In order to learn more about ARX function, we have studied in detail Arx expression in the central nervous system during mouse embryonic development as well as in the adult. During early stages of development, Arx is expressed in a significant proportion of neurons in the cortex, the striatum, the ganglionic eminences and also in the spinal cord. In the adult, expression of Arx is still present and restricted to regions that are known to be rich in GABAergic neurons such as the amygdala and the olfactory bulb. A possible role for Arx in this type of neurons is further reinforced by the expression of Arx in a subset of GABAergic interneurons in young and mature primary cultures of cortical neuronal cells as well as in vivo. Moreover, these data could explain the occurrence of seizures in the great majority of patients with an ARX mutation, due to mislocalisation or dysfunction of GABAergic neurons. We also performed ARX wild-type and mutant over-expression experiments and found that the different ARX mutations tested did not modify the morphology of the cells. Moreover, no abnormal cell death or protein aggregation was observed, hence suggesting that more subtle pathogenic mechanisms are involved.

DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains.

A down-regulation of reelin and glutamic acid decarboxylase (GAD) 67 mRNAs was detected in gamma-aminobutyric acid (GABA)ergic cortical interneurons of schizophrenia (SZ) postmortem brains (10), suggesting that the availability of GABA and reelin may be decreased in SZ cortex. In situ hybridization of the mRNA encoding for DNA-methyltransferase 1, which catalyzes the methylation of promoter CpG islands, shows that the expression of this mRNA is increased in cortical GABAergic interneurons but not in pyramidal neurons of SZ brains. Counts of reelin mRNA-positive neurons in Brodmann's area 10 of either nonpsychiatric subjects or SZ patients show that the expression of reelin mRNA is decreased in layer-I, -II, and -IV GABAergic interneurons of SZ patients. These findings are consistent with the hypothesis that the increase of DNA-methyltransferase 1 expression in telencephalic GABAergic interneurons of SZ patients causes a promoter hypermethylation of reelin and GAD(67) and perhaps of other genes expressed in these interneurons. It is difficult to decide whether this dysfunction of GABAergic neurons detected in SZ is responsible for this disease or is a consequence of this disorder. Although at present we cannot differentiate between these two alternatives, it is important to consider that so far a molecular pathology of cortical GABAergic neurons appears to be the most consistent finding associated with SZ morbidity.