GABA receptor knockdown in prefrontal cortex induces behavioral aberrations associated with autism spectrum disorder in mice.

Autism spectrum disorder (ASD) is a set of heterogeneous neurodevelopmental disorders, characterized by social interaction deficit, stereotyped or repetitive behaviors. Apart from these core symptoms, a great number of individuals with ASD exhibit higher levels of anxiety and memory deficits. Previous studies demonstrate pronounced decrease of γ-aminobutyric acid B1 receptor (GABAR) protein level of frontal lobe in both ASD patients and animal models. The aim of the present study was to determine the role of GABAR in ASD-related behavioral aberrations. Herein, the protein and mRNA levels of GABAR in the prefrontal cortex (PFC) of sodium valproic acid (VPA)-induced mouse ASD model were determined by Western blot and qRT-PCR analysis, respectively. Moreover, the behavioral abnormalities in naive mice with GABAR knockdown mediated by recombinant adeno-associated virus (rAAV) were assessed in a comprehensive test battery consisted of social interaction, marble burying, self-grooming, open-field, Y-maze and novel object recognition tests. Furthermore, the action potential changes induced by GABAR deficiency were examined in neurons within the PFC of mouse. The results show that the mRNA and protein levels of GABAR in the PFC of prenatal VPA-induced mouse ASD model were decreased. Concomitantly, naive mice with GABAR knockdown exhibited ASD-like behaviors, such as impaired social interaction and communication, elevated stereotypes, anxiety and memory deficits. Patch-clamp recordings also revealed that GABAR knockdown provoked enhanced neuronal excitability by increasing action potential discharge frequencies. Overall, these findings support a notion that GABAR deficiency might contribute to ASD-like phenotypes, with the pathogenesis most likely resulting from enhanced neuronal excitability. SUBHEADINGS: GABA Knockdown Induces Behavioral Aberrations with ASD.