Abstract
Autism spectrum disorder (ASD) is a neuronal developmental disorder with impaired social interaction and communication, often with abnormal intelligence and comorbidity with epilepsy. Disturbances in synaptic transmission, including the GABAergic, glutamatergic, and serotonergic systems, are known to be involved in the pathogenesis of this disorder, yet we do not know if there is a common molecular mechanism. As mutations in the GABAergic receptor subunit gene GABRA4 are reported in patients with ASD, we eliminated the Gabra4 gene in mice and found that the Gabra4 knockout mice showed autistic-like behavior, enhanced spatial memory, and attenuated susceptibility to pentylenetetrazol-induced seizures, a constellation of symptoms resembling human high-functioning autism. To search for potential molecular pathways involved in these phenotypes, we performed a hippocampal transcriptome profiling, constructed a hippocampal interactome network, and revealed an upregulation of the NMDAR system at the center of the converged pathways underlying high-functioning autism-like and anti-epilepsy phenotypes.
Highlights
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with core clinical features of impaired social interaction, and communication withdrawal, stereotyped behaviors, and restricted interests [1, 2]
When a novel mouse was introduced into the previously empty cage, the WT mice preferred to sniff the novel mice, while the Gabra4−/− mice did not show this preference (Fig. 1b), suggesting a deficit in social-novelty seeking in the mutant mice. These results demonstrated that the Gabra4−/− mice exhibited reduced social interaction tendencies, which are characteristic features of autism
To exclude the possibility that social deficits might have resulted from locomotor dysfunction, we evaluated locomotor performance in the open field test and found that WT and Gabra4−/− mice had no significant differences in the total distance traveled (Additional file 1: Figure S1C)
Summary
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with core clinical features of impaired social interaction, and communication withdrawal, stereotyped behaviors, and restricted interests [1, 2]. Individuals with autism show a wide range of variations in intelligence quotient (IQ); it can be normal, above average, or with intellectual disability. About 55% show intellectual disability (IQ < 70) [3] and 30% of children with autism may have severe intellectual disability [4]. ASD without an intellectual disability is called high-functioning autism (HF-ASD) [4]. About 20–30% of autistic children show symptoms of epilepsy [5, 6], whereas HF-ASD individuals have a lower incidence of epilepsy [7, 8].
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