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

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Abstract

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.

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Acknowledgments

The authors would like to thank OxBioSci for editing the English in this manuscript and all of the research participants. This study was supported by grants MOST 105-2628-B-010-006–MY3, MOST 104-2314-B-006-030-MY3, MOST 103-2321-B-010-016, and MOST 99-2628-B-006-013-MY3 from the Ministry of Science and Technology of Taiwan. This study was also supported by Yen Tjing Ling Medical Foundation, Taiwan (CI-105-12); National Yang-Ming University-Far Eastern Memorial Hospital Joint Research Program (#NYMU-FEMH 106DN09); the Brain Research Center, National Yang-Ming University; and a grant from Ministry of Education, Aim for the Top University Plan, Taiwan. The funding institutions of this study had no further role in the study design, the collection, analysis, and interpretation of data; the writing of this paper; or the decision to submit it for publication.

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Authors and Affiliations

  1. Department and Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan

    Han-Fang Wu, Ya-Ting Hsu, Chi-Wei Lee, Yi-Ju Chen & Hui-Ching Lin

  2. Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan

    Po See Chen & Tzu-Feng Wang

  3. Addiction Research Center, National Cheng Kung University, Tainan, 70101, Taiwan

    Po See Chen

  4. Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Cheng Kung University and Academia Sinica, Taipei, Taiwan

    Tzu-Feng Wang

  5. Brain Research Center, National Yang-Ming University, Taipei, 11221, Taiwan

    Hui-Ching Lin

  6. Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan

    Hui-Ching Lin

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HC Lin and PS Chen conceived and designed the experiments. HF Wu, YT Hsu, CW Lee, TF Wang, and YJ Chen performed the experiments. HF Wu and PS Chen analyzed the data. PS Chen contributed reagents/materials/analysis tools. HF Wu and HC Lin wrote the paper.

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Correspondence to Hui-Ching Lin.

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Wu, HF., Chen, P.S., Hsu, YT. et al. D-Cycloserine Ameliorates Autism-Like Deficits by Removing GluA2-Containing AMPA Receptors in a Valproic Acid-Induced Rat Model. Mol Neurobiol 55, 4811–4824 (2018). https://doi.org/10.1007/s12035-017-0685-1

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