Dataset Information

Enhancement of inhibitory neurotransmission by GABAA receptors having ?2,3-subunits ameliorates behavioral deficits in a mouse model of autism.

ABSTRACT: 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 ?2,3-subunit-selective positive allosteric modulator L-838,417 was effective, but the ?1-subunit-selective drug zolpidem exacerbated social deficits. Impaired GABAergic neurotransmission may contribute to ASD, and ?2,3-subunit-selective positive GABAA receptor modulation may be an effective treatment.

SUBMITTER: Han S

PROVIDER: S-EPMC4079471 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Enhancement of inhibitory neurotransmission by GABAA receptors having α2,3-subunits ameliorates behavioral deficits in a mouse model of autism.

Han Sung S Tai Chao C Jones Christina J CJ Scheuer Todd T Catterall William A WA

Neuron 20140301 6

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 alloste ...[more]

PMID: 24656250

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Project description:BACKGROUND:Inhibitory control deficits are common in autism spectrum disorder (ASD) and associated with more severe repetitive behaviors. Inhibitory control deficits may reflect slower execution of stopping processes, or a reduced ability to delay the onset of behavioral responses in contexts of uncertainty. Previous studies have documented relatively spared stopping processes in ASD, but whether inhibitory control deficits in ASD reflect failures to delay response onset has not been systematically assessed. Further, while improvements in stopping abilities and response slowing are seen through adolescence/early adulthood in health, their development in ASD is less clear. METHODS:A stop-signal test (SST) was administered to 121 individuals with ASD and 76 age and IQ-matched healthy controls (ages 5-28). This test included 'GO trials' in which participants pressed a button when a peripheral target appeared and interleaved 'STOP trials' in which they were cued to inhibit button-presses when a stop-signal appeared at variable times following the GO cue. STOP trial accuracy, RT of the stopping process (SSRT), and reaction time (RT) slowing during GO trials were examined. RESULTS:Relative to controls, individuals with ASD had reduced accuracy on STOP trials. SSRTs were similar across control and ASD participants, but RT slowing was reduced in patients compared to controls. Age-related increases in stopping ability and RT slowing were attenuated in ASD. Reduced stopping accuracy and RT slowing were associated with more severe repetitive behaviors in ASD. DISCUSSION:Our findings show that inhibitory control deficits in ASD involve failures to strategically delay behavioral response onset. These results suggest that reduced preparatory behavioral control may underpin inhibitory control deficits as well as repetitive behaviors in ASD. Typical age-related improvements in inhibitory control during late childhood/early adolescence are reduced in ASD, highlighting an important developmental window during which treatments may mitigate cognitive alterations contributing to repetitive behaviors.

Dataset Information

Enhancement of inhibitory neurotransmission by GABAA receptors having ?2,3-subunits ameliorates behavioral deficits in a mouse model of autism.

Publications

Enhancement of inhibitory neurotransmission by GABAA receptors having α2,3-subunits ameliorates behavioral deficits in a mouse model of autism.

Similar Datasets

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