GABAA Receptor Downregulation in Brains of Subjects with Autism

School of Medicine, University of Minnesota Department of Neuroscience Minneapolis MN USA
Journal of Autism and Developmental Disorders (Impact Factor: 3.34). 02/2008; 39(2):223-230. DOI: 10.1007/s10803-008-0646-7


Gamma-aminobutyric acid A (GABAA) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain. Preliminary
reports have demonstrated altered expression of GABA receptors in the brains of subjects with autism suggesting GABA/glutamate
system dysregulation. We investigated the expression of four GABAA receptor subunits and observed significant reductions in GABRA1, GABRA2, GABRA3, and GABRB3 in parietal cortex (Brodmann’s
Area 40 (BA40)), while GABRA1 and GABRB3 were significantly altered in cerebellum, and GABRA1 was significantly altered in
superior frontal cortex (BA9). The presence of seizure disorder did not have a significant impact on GABAA receptor subunit expression in the three brain areas. Our results demonstrate that GABAA receptors are reduced in three brain regions that have previously been implicated in the pathogenesis of autism, suggesting
widespread GABAergic dysfunction in the brains of subjects with autism.

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Available from: S.Hossein Fatemi
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    • "Using qRT-PCR, we validated the upregulation of glutamate receptor subunit GRIK1 and the downregulation of GABA receptor subunit GABRA3. Dysregulation of either gene would suggest perturbations in neuronal signalling and function; interestingly, decreased expression of GABRA3 has been found in brains of patients with autism spectrum disorder[26,27]and a truncating mutation has been found in a male with ASD[28]. In addition, we observed downregulation of transcripts for voltage-gated Na + and K + channels in WBS neurons. "
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    ABSTRACT: Williams-Beuren Syndrome (WBS) is caused by the microdeletion of approximately 25 genes on chromosome 7q11.23, and is characterized by a spectrum of cognitive and behavioural features. We generated cortical neurons from a WBS individual and unaffected (WT) control by directed differentiation of induced pluripotent stem cells (iPSCs). Single cell mRNA analyses and immunostaining demonstrated very efficient production of differentiated cells expressing markers of mature neurons of mixed subtypes and from multiple cortical layers. We found that there was a profound alteration in action potentials, with significantly prolonged WBS repolarization times and a WBS deficit in voltage-activated K + currents. Miniature excitatory synaptic currents were normal, indicating that unitary excitatory synaptic transmission was not altered. Gene expression profiling identified 136 negatively enriched gene sets in WBS compared to WT neurons including gene sets involved in neurotransmitter receptor activity, synaptic assembly, and potassium channel complexes. Our findings provide insight into gene dysregulation and electrophysiological defects in WBS patient neurons.
    Full-text · Article · Dec 2015 · Molecular Brain
    • ") (Fatemi et al. 2009a , b , 2010a , 2014 ). GABRα1, GABRβ3, GABBR1, and GABA B receptor 2 (GABBR2) proteins were significantly decreased in cerebella obtained from subjects with autism vs. matched controls (Fig. 16.3 "
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    ABSTRACT: Autism is a heterogeneous neurodevelopmental disorder. The etiology of autism remains unknown although both genetic and environmental factors are likely to be involved. These factors disrupt the course of normal brain development from the cellular to the gross anatomical levels. The Reelin, gamma-aminobutyric acid (GABA), and fragile X mental retardation protein (FMRP)-metabotropic glutamate receptor 5 (mGluR5) signaling systems play important roles during the development of the nervous system. Disruption of these pathways is likely to lead to altered synaptic transmission and, ultimately, the cognitive and behavioral deficits associated with autism. This chapter describes each of these signaling systems and summarizes the current evidence that link them to autism. Therapies that target molecules in these signaling systems may provide new means of treating the core symptoms of autism.
    No preview · Article · Jan 2015
    • "Bullock et al. (2008) found no change in GABRβ3 mRNA expression in the lateral cerebella of subjects with schizophrenia (Bullock et al., 2008). We identified significant reductions in GABRβ3 protein in the cerebellum and BA40 of subjects with autism (Fatemi et al., 2009a) (Table 1). Similarly, reduced GABRβ3 protein expression has also been reported in the PFC of subjects with autism (Samaco et al., 2005). "
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    ABSTRACT: Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. GABAergic receptor abnormalities have been documented in several major psychiatric disorders including schizophrenia, mood disorders, and autism. Abnormal expression of mRNA and protein for multiple GABA receptors has also been observed in multiple brain regions leading to alterations in the balance between excitatory/inhibitory signaling in the brain with potential profound consequences for normal cognition and maintenance of mood and perception. Altered expression of GABAA receptor subunits has been documented in fragile X mental retardation 1 (FMR1) knockout mice, suggesting that loss of its protein product, fragile X mental retardation protein (FMRP), impacts GABAA subunit expression. Recent postmortem studies from our laboratory have shown reduced expression of FMRP in the brains of subjects with schizophrenia, bipolar disorder, major depression, and autism. FMRP acts as a translational repressor and, under normal conditions, inhibits metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. In fragile X syndrome (FXS), the absence of FMRP is hypothesized to lead to unregulated mGluR5 signaling, ultimately resulting in the behavioral and intellectual impairments associated with this disorder. Our laboratory has identified changes in mGluR5 expression in autism, schizophrenia, and mood disorders. In the current review article, we discuss our postmortem data on GABA receptors, FMRP, and mGluR5 levels and compare our results with other laboratories. Finally, we discuss the interactions between these molecules and the potential for new therapeutic interventions that target these interconnected signaling systems. Copyright © 2014 Elsevier B.V. All rights reserved.
    No preview · Article · Nov 2014 · Schizophrenia Research
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