D-Cycloserine Ameliorates Autism-Like Deficits by Removing GluA2-Containing AMPA Receptors in a Valproic Acid-Induced Rat Model
- 333 Downloads
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.
KeywordsAutism spectrum disorder D-Cycloserine Long-term depression NMDARs GluA2/AMPARs Valproic acid
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.
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.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflicts of interest.
- 1.Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J (1996) Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol 370(2):247–261. doi: 10.1002/(SICI)1096-9861(19960624)370:2<247::AID-CNE8>3.0.CO;2-2 CrossRefPubMedGoogle Scholar
- 13.van Berckel BN, Evenblij CN, van Loon BJ, Maas MF, van der Geld MA, Wynne HJ, van Ree JM, Kahn RS (1999) D-cycloserine increases positive symptoms in chronic schizophrenic patients when administered in addition to antipsychotics: a double-blind, parallel, placebo-controlled study. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 21(2):203–210. doi: 10.1016/S0893-133X(99)00014-7 CrossRefGoogle Scholar
- 14.Ren J, Li X, Zhang X, Li M, Wang Y, Ma Y (2013) The effects of intra-hippocampal microinfusion of D-cycloserine on fear extinction, and the expression of NMDA receptor subunit NR2B and neurogenesis in the hippocampus in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 44:257–264. doi: 10.1016/j.pnpbp.2013.02.017 CrossRefGoogle Scholar
- 18.Minshawi NF, Wink LK, Shaffer R, Plawecki MH, Posey DJ, Liu H, Hurwitz S, McDougle CJ et al (2016) A randomized, placebo-controlled trial of D-cycloserine for the enhancement of social skills training in autism spectrum disorders. Molecular Autism 7:2. doi: 10.1186/s13229-015-0062-8 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Blundell J, Blaiss CA, Etherton MR, Espinosa F, Tabuchi K, Walz C, Bolliger MF, Sudhof TC et al (2010) Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience 30(6):2115–2129. doi: 10.1523/JNEUROSCI.4517-09.2010 CrossRefGoogle Scholar
- 20.Ramanathan S, Woodroffe A, Flodman PL, Mays LZ, Hanouni M, Modahl CB, Steinberg-Epstein R, Bocian ME et al (2004) A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R. BMC Med Genet 5:10. doi: 10.1186/1471-2350-5-10 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Nakamoto M, Nalavadi V, Epstein MP, Narayanan U, Bassell GJ, Warren ST (2007) Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors. Proc Natl Acad Sci U S A 104(39):15537–15542. doi: 10.1073/pnas.0707484104 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Wu HF, Chen PS, Chen YJ, Lee CW, Chen IT, Lin HC (2016) Alleviation of N-methyl-D-aspartate receptor-dependent long-term depression via regulation of the glycogen synthase kinase-3beta pathway in the amygdala of a valproic acid-induced animal model of autism. Mol Neurobiol. doi: 10.1007/s12035-016-0074-1
- 31.Pyter LM, Pineros V, Galang JA, McClintock MK, Prendergast BJ (2009) Peripheral tumors induce depressive-like behaviors and cytokine production and alter hypothalamic-pituitary-adrenal axis regulation. Proc Natl Acad Sci U S A 106(22):9069–9074. doi: 10.1073/pnas.0811949106 CrossRefPubMedPubMedCentralGoogle Scholar
- 45.Chen YW, Lin HC, Ng MC, Hsiao YH, Wang CC, Gean PW, Chen PS (2014) Activation of mGluR2/3 underlies the effects of N-acetylcystein on amygdala-associated autism-like phenotypes in a valproate-induced rat model of autism. Front Behav Neurosci 8:219. doi: 10.3389/fnbeh.2014.00219 PubMedPubMedCentralGoogle Scholar
- 52.Lee E, Lee J, Kim E (2016) Excitation/inhibition imbalance in animal models of autism spectrum disorders. Biol Psychiatry. doi: 10.1016/j.biopsych.2016.05.011
- 57.Adeleye A, Shohami E, Nachman D, Alexandrovich A, Trembovler V, Yaka R, Shoshan Y, Dhawan J et al (2010) D-cycloserine improves functional outcome after traumatic brain injury with wide therapeutic window. Eur J Pharmacol 629(1–3):25–30. doi: 10.1016/j.ejphar.2009.11.066 CrossRefPubMedGoogle Scholar
- 64.Mejias R, Adamczyk A, Anggono V, Niranjan T, Thomas GM, Sharma K, Skinner C, Schwartz CE et al (2011) Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism. Proc Natl Acad Sci U S A 108(12):4920–4925. doi: 10.1073/pnas.1102233108 CrossRefPubMedPubMedCentralGoogle Scholar
- 72.Gupta SC, Yadav R, Pavuluri R, Morley BJ, Stairs DJ, Dravid SM (2015) Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity. Neuropharmacology 93:274–284. doi: 10.1016/j.neuropharm.2015.02.013 CrossRefPubMedPubMedCentralGoogle Scholar
- 74.Radley JJ, Johnson LR, Janssen WG, Martino J, Lamprecht R, Hof PR, LeDoux JE, Morrison JH (2006) Associative Pavlovian conditioning leads to an increase in spinophilin-immunoreactive dendritic spines in the lateral amygdala. Eur J Neurosci 24(3):876–884. doi: 10.1111/j.1460-9568.2006.04962.x CrossRefPubMedGoogle Scholar