Enhancement of Inhibitory Neurotransmission by GABA A Receptors Having α 2,3 -Subunits Ameliorates Behavioral Deficits in a Mouse Model of Autism
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Autism spectrum disorder (ASD) may arise from increased ratio of excitatory to inhibitory neurotransmission in the brain. Many pharmacological treatments have been tested in ASD, but only limited success has been achieved. Here we report that BTBR T(+)Itpr3(tf)/J (BTBR) mice, a model of idiopathic autism, have reduced spontaneous GABAergic neurotransmission. Treatment with low nonsedating/nonanxiolytic doses of benzodiazepines, which increase inhibitory neurotransmission through positive allosteric modulation of postsynaptic GABAA receptors, improved deficits in social interaction, repetitive behavior, and spatial learning. Moreover, negative allosteric modulation of GABAA receptors impaired social behavior in C57BL/6J and 129SvJ wild-type mice, suggesting that reduced inhibitory neurotransmission may contribute to social and cognitive deficits. The dramatic behavioral improvement after low-dose benzodiazepine treatment was subunit specific-the α2,3-subunit-selective positive allosteric modulator L-838,417 was effective, but the α1-subunit-selective drug zolpidem exacerbated social deficits. Impaired GABAergic neurotransmission may contribute to ASD, and α2,3-subunit-selective positive GABAA receptor modulation may be an effective treatment.
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Enhancing GABAergic activity in BTBR mice ameliorates their social impairment.
“Enhancing GABAergic activity in BTBR mice ameliorates their social impairment, and negative allosteric GABA modulation in C57Bl6J mice recapitulates social impairment.48”
From Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment (2016) · cites this paper as [48]
Negative allosteric GABA modulation in C57Bl6J mice recapitulates social impairment.
“Enhancing GABAergic activity in BTBR mice ameliorates their social impairment, and negative allosteric GABA modulation in C57Bl6J mice recapitulates social impairment.48”
From Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment (2016) · cites this paper as [48]
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References 85 · Cited by 231
- Authors
- Han, S., Tai, C., Jones, C. J., Scheuer, T., & Catterall, W. A.
- Affiliations
- University of Washington (US)
- Corresponding author
- Catterall, William A.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 81
- Issue
- 6
- Pages
- 1282-1289
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4079471
- OpenAlex
- W1993056315
- Cited by
- 231
- References
- 85
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 5 · 2023: 21 · 2022: 13 · 2021: 21 · 2020: 12 · 2019: 20 · 2018: 18 · 2017: 28 · 2016: 23 · 2015: 27 · 2014: 15
- FWCI
- 14.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R0-1 NS25704, R01NS025704)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD02274, U54HD083091, P30HD002274)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, GABAA receptor, positive allosteric modulation, negative allosteric modulation, benzodiazepines, zolpidem, BTBR mice, social interaction deficits, repetitive behavior, spatial learning, excitation-inhibition balance, GABAergic neurotransmission
- MeSH terms
- Zolpidem, Animals, Autistic Disorder, Behavior, Animal, Benzodiazepines, Brain, Disease Models, Animal, Fluorobenzenes, Interpersonal Relations, Male, Mice, Inbred C57BL, Synaptic Transmission, Pyridines, Receptors, GABA-A, Social Behavior, Triazoles, Protein Subunits, Mice, Mice, 129 Strain
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