D-Cycloserine Ameliorates Autism-Like Deficits by Removing GluA2-Containing AMPA Receptors in a Valproic Acid-Induced Rat Model

Han Fang Wu, Po See Chen, Ya Ting Hsu, Chi Wei Lee, Tzu Feng Wang, Yi Ju Chen, Hui Ching Lin*

*此作品的通信作者

研究成果: Article同行評審

20 引文 斯高帕斯(Scopus)

摘要

Valproic acid (VPA)-exposed rat offspring have demonstrated autism spectrum disorder (ASD) phenotypes and impaired N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) in the lateral nucleus of the amygdala. NMDAR partial agonist D-cycloserine (DCS) has been reported to act as a cognitive enhancer by increasing the NMDAR response to improve autistic-like phenotypes in animals. However, the mechanism of DCS in alleviating the ASD is still unknown. Using combined behavioral, electrophysiological, and molecular approaches, we found that DCS administration rescued social interaction deficits and anxiety/repetitive-like behaviors observed in VPA-exposed offspring. In the amygdala synapses, DCS treatment reversed the decreased paired pulse ratio (PPR) and the impaired NMDAR-dependent LTD, increased the frequency and amplitude of miniature excitatory post-synaptic currents (mEPSCs), and resulted in a higher dendritic spine density at the amygdala synapses in the VPA-exposed offspring. Moreover, we found that DCS facilitated the removal of GluA2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (GluA2/AMPARs) by inducing NMDAR-dependent LTD in the VPA-exposed offspring. We further established that the effects of DCS treatment, including increased GluA2/AMPAR removal and rescues of impaired social behavior, were blocked by Tat-GluA23Y, a GluA2-derived peptide that disrupted regulation of AMPAR endocytosis. These results provided the first evidence that rescue of the ASD-like phenotype by DCS is mediated by the mechanism of GluA2/AMPAR removal in VPA-exposed rat offspring.

原文English
頁(從 - 到)4811-4824
頁數14
期刊Molecular Neurobiology
55
發行號6
DOIs
出版狀態Published - 1 6月 2018

指紋

深入研究「D-Cycloserine Ameliorates Autism-Like Deficits by Removing GluA2-Containing AMPA Receptors in a Valproic Acid-Induced Rat Model」主題。共同形成了獨特的指紋。

引用此