Genetic association has been found between the GABRB1 gene and autism. Positive associations were found in particular through interaction with GABRA4 (Ma et al., 2005) and in families with a positive history of seizures (Collins et al., 2006).
Molecular Function
The encoded protein is a subunit of the GABA-A receptor. Neurotransmission is predominantly mediated by a gated chloride channel activity intrinsic to the receptor.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism.
Altered GABAergic inhibitory transmission has been implicated in autism, with mutations in GABA-A receptors having been identified as genetic underpinnings to the disease. The Gabrb1 mutant model provides further evidence of this, exhibiting alterations in behavior. Specifically, mutant mice display decreased social interaction and increased grooming, with no change in general locomotor activity or anxiety. The model also shows upregulated NMDARs and NMDAR-currents, with increased levels of GluN1 and GluN2B in the hippocampus. Additionally, Gabrb1 mutant mice exhibit increased learning, displaying heightened responses to fear conditioning as well as enhanced susceptibility to picrotoxin-induced seizures. Alterations in social interaction, grooming, learning, and seizure susceptibility were all rescued by treatment with the NMDAR antagonist memantine or the glutamine synthetase antagonist methionine sulfoximine.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Gabrb1 knockout C57BL/6J mice were generated by TALEN (transcription activator-like effector nuclease). Exon 1 of the mouse Gabrb1 gene (chr5: 71857359-72294152, NCBI Reference Sequence: NC_000071.7) was chosen as the TALEN target site. TALEN mRNAs were generated by in vitro transcription and then injected into fertilized eggs.
Allele Type: Knockout
Strain of Origin: Not specified
Genetic Background: C57BL/6J
ES Cell Line: Not specified
Mutant ES Cell Line: Model Source: Cyagen Biosciences Inc.
Description: NMDAR-currents were increased in hippocampal CA1 neurons in Gabrb1 mutant mice compared to wildtype controls, while the AMPAR-currents were unchanged.
Exp Paradigm: CA1 neurons
Description: 8 of 12 Gabrb1 mutant male mice (66.67%) and 3 of 14 wildtype male mice (21.43%) died after picrotoxin injection, showing significantly higher severity of symptoms in Gabrb1 mutant mice. However, no difference in lethality was observed between the mutant and wildtype female mice.
Exp Paradigm: Picrotoxin administration
Description: In the home cage social interaction test, Gabrb1 mutant mice spent less time engaged in exploring a stranger mouse, an active social interaction, compared to wildtype controls.
Description: Gabrb1 mutant mice showed less preference for sniffing the stranger 2 mouse rather than the familiar stranger 1 mouse, with no difference in the time spent in either chamber. This was further exhibited by a decreased Preference Index.
Exp Paradigm: novel mouse (stranger 2) vs. familiar mouse (stranger 1)
Description: During the training trials, Gabrb1 mutant and wildtype control mice showed significant improvement in escape latency time to find the hidden platform, with Gabrb1 performing significantly faster than the wildtype mice. Further, the swimming velocity for the Gabrb1 mutant mice was not different compared with wildtype controls.
Description: Gabrb1 mutant mice showed increased fear memory compared to wildtype controls in the test phase of the fear conditioning test, with a significantly higher percentage of freezing time.
Exp Paradigm: 24 hours after fear conditioning
Description: The samples of Gabrb1 knockout mice were well separated from those of wildtype mice in principal component analysis (PCA) by 86% variance, suggesting a consistent transcriptomic difference between the knockout mice and WT mice. Out of 16,403 expressed genes in the brain, 1,587 were identified as differentially expressed genes, including 916 upregulated genes and 671 down-regulated genes.
Description: GluN1 and GluN2B were upregulated in both the extrasynaptic and synaptic fractions of Gabrb1 mutant mouse hippocampi.
Exp Paradigm: hippocampus
Description: Immunostaining of hippocampal slices for GS (encoding by Glul) and SLC38A3 in astrocytes, showed significant upregulation of GS and SLC38A3 in CA1 GFAP+ astrocytes of Gabrb1 mutant mice compared to wildtype controls.
Exp Paradigm: CA1 neurons
Description: Immunoprecipitation of the endogenous SHANK3 protein confirmed SHANK3-GluN1 and SHANK3-GluN2B interactions in the mouse hippocampus.
Exp Paradigm: hippocampus
Description: Gabrb1 mutant mice exhibited significantly decreased mRNA expression levels of the Gabrb1 gene in the hippocampus compared to wildtype controls.
Exp Paradigm: hippocampus
Description: Differentially expressed genes were compared with candidate gene sets for ASD, epilepsy, and learning/memory. The up-regulated genes showed enrichment with ASD candidate genes, epilepsy candidate genes, and learning/memory-related genes, suggesting that the upregulation of these genes may be involved in determining the phenotypes observed in Gabrb1 mutant mice. Additionally, DEGs in astrocytes showed enrichment with ASD, epilepsy, and learning/memory genes, suggesting that the DEGs in astrocytes might contain the signaling pathways underlying the autistic-like phenotypes, enhanced learning/memory, and increased susceptibility to seizure.
Exp Paradigm: UMAP
