Generational synaptic functions of GABAA receptor β3 subunit deteriorations in an animal model of social deficit

Journal of Biomedical Science

Research

Chi-Wei Lee¹  Ming-Chia Chu¹  Han-Fang Wu¹  Yueh-Jung Chung¹  Hsiang Chi¹  Hui-Ching Lin²  Po See Chen³ 

[1] Department and Institute of Physiology, School of Medicine, National Yang Ming Chiao Tung University, 112, Taipei, Taiwan;Department and Institute of Physiology, School of Medicine, National Yang Ming Chiao Tung University, 112, Taipei, Taiwan;Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, 110, Taipei, Taiwan;Brain Research Center, National Yang Ming Chiao Tung University, 112, Taipei, Taiwan;Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 704, Tainan, Taiwan;Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, 704, Tainan, Taiwan;

关键词: GABAR;    Excitatory/inhibitory imbalance;    Gephyrin;    Generational effect;    Valproate;    Autism spectrum disorder;   

DOI  :  10.1186/s12929-022-00835-w

 received in 2022-04-01, accepted in 2022-07-06,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundDisruption of normal brain development is implicated in numerous psychiatric disorders with neurodevelopmental origins, including autism spectrum disorder (ASD). Widespread abnormalities in brain structure and functions caused by dysregulations of neurodevelopmental processes has been recently shown to exert adverse effects across generations. An imbalance between excitatory/inhibitory (E/I) transmission is the putative hypothesis of ASD pathogenesis, supporting by the specific implications of inhibitory γ-aminobutyric acid (GABA)ergic system in autistic individuals and animal models of ASD. However, the contribution of GABAergic system in the neuropathophysiology across generations of ASD is still unknown. Here, we uncover profound alterations in the expression and function of GABAA receptors (GABAARs) in the amygdala across generations of the VPA-induced animal model of ASD.MethodsThe F2 generation was produced by mating an F1 VPA-induced male offspring with naïve females after a single injection of VPA on embryonic day (E12.5) in F0. Autism-like behaviors were assessed by animal behavior tests. Expression and functional properties of GABAARs and related proteins were examined by using western blotting and electrophysiological techniques.ResultsSocial deficit, repetitive behavior, and emotional comorbidities were demonstrated across two generations of the VPA-induced offspring. Decreased synaptic GABAAR and gephyrin levels, and inhibitory transmission were found in the amygdala from two generations of the VPA-induced offspring with greater reductions in the F2 generation. Weaker association of gephyrin with GABAAR was shown in the F2 generation than the F1 generation. Moreover, dysregulated NMDA-induced enhancements of gephyrin and GABAAR at the synapse in the VPA-induced offspring was worsened in the F2 generation than the F1 generation. Elevated glutamatergic modifications were additionally shown across generations of the VPA-induced offspring without generation difference.ConclusionsTaken together, these findings revealed the E/I synaptic abnormalities in the amygdala from two generations of the VPA-induced offspring with GABAergic deteriorations in the F2 generation, suggesting a potential therapeutic role of the GABAergic system to generational pathophysiology of ASD.

【 授权许可】

CC BY   
© The Author(s) 2022. corrected publication [2023]

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