GABAB1 receptor knockdown in prefrontal cortex induces behavioral aberrations associated with autism spectrum disorder in mice

Abstract

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 (GABA_B1R) protein level of frontal lobe in both ASD patients and animal models. The aim of the present study was to determine the role of GABA_B1R in ASD-related behavioral aberrations. Herein, the protein and mRNA levels of GABA_B1R 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 GABA_B1R 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 GABA_B1R deficiency were examined in neurons within the PFC of mouse. The results show that the mRNA and protein levels of GABA_B1R in the PFC of prenatal VPA-induced mouse ASD model were decreased. Concomitantly, naive mice with GABA_B1R knockdown exhibited ASD-like behaviors, such as impaired social interaction and communication, elevated stereotypes, anxiety and memory deficits. Patch-clamp recordings also revealed that GABA_B1R knockdown provoked enhanced neuronal excitability by increasing action potential discharge frequencies. Overall, these findings support a notion that GABA_B1R deficiency might contribute to ASD-like phenotypes, with the pathogenesis most likely resulting from enhanced neuronal excitability. SUBHEADINGS: GABA_B1 Knockdown Induces Behavioral Aberrations with ASD.

Keywords: Action potential; Autism spectrum disorder; GABA(B1) receptor; Mouse model; Prefrontal cortex.