title: Alleviation of N-Methyl-D-Aspartate Receptor-Dependent Long-Term Depression via Regulation of the Glycogen Synthase Kinase-3β Pathway in the Amygdala of a Valproic Acid-Induced Animal Model of Autism.
abstract: The amygdala plays crucial roles in socio-emotional behavior and cognition, both of which are abnormal in autism spectrum disorder (ASD). Valproic acid (VPA)-exposed rat offspring have demonstrated ASD phenotypes and amygdala excitatory/inhibitory imbalance. However, the role of glutamatergic synapses in this imbalance remains unclear. In this study, we used a VPA-induced ASD-like model to assess glutamatergic synapse-dependent long-term depression (LTD) and depotentiation (DPT) in the amygdala. We first confirmed that the VPA-exposed offspring exhibited sociability deficits, anxiety, depression-like behavior, and abnormal nociception thresholds. Then, electrophysiological examination showed a significantly decreased paired-pulse ratio in the amygdala. In addition, both NMDA-dependent LTD and DPT were absent from the amygdala. Furthermore, we found that the levels of glycogen synthase kinase3β (GSK-3β) phosphorylation and β-catenin were significantly higher in the amygdala of the experimental animals than in the controls. Local infusion of phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin into the amygdala reversed the increased phosphorylation level and impaired social behavior. Taken together, the results suggested that NMDA receptor-related synaptic plasticity is dysfunctional in VPA-exposed offspring. In addition, GSK-3β in the amygdala is critical for synaptic plasticity at the glutamatergic synapses and is related to social behavior. Its role in the underlying mechanism of ASD merits further investigation.
authors: Department and Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan.
authors: Han-Fang
authors: HF
authors: Wu
authors: Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Addiction Research Center, National Cheng Kung University, Tainan, Taiwan.
authors: Po See
authors: PS
authors: Chen
authors: Department and Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan.
authors: Yi-Ju
authors: YJ
authors: Chen
authors: Department and Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan.
authors: Chi-Wei
authors: CW
authors: Lee
authors: Department and Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan.
authors: I-Tuan
authors: IT
authors: Chen
authors: Department and Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan. hclin7@ym.edu.tw.|Brain Research Center, National Yang-Ming University, Taipei, 11221, Taiwan. hclin7@ym.edu.tw.|Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan. hclin7@ym.edu.tw.
authors: Hui-Ching
authors: HC
authors: Lin
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000378:metabolism*; D003863:Depression / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012919:Social Behavior; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D014635:Valproic Acid; D000071679:Glycogen Synthase Kinase 3 beta
keywords: Amygdala; Autism spectrum disorder; GSK-3β; Long-term depression; N-Methyl-D-aspartate receptor; Valproic acid