MeCP2 Modulates Sex Differences in the Postsynaptic Development of the Valproate Animal Model of Autism
Abstract
Males are predominantly affected by autism spectrum disorders (ASD) with a prevalence ratio of 5:1. However, the underlying pathological mechanisms governing the male preponderance of ASD remain unclear. Recent studies suggested that epigenetic aberrations may cause synaptic dysfunctions, which might be related to the pathophysiology of ASD. In this study, we used rat offspring prenatally exposed to valproic acid (VPA) as an animal model of ASD. We found male-selective abnormalities in the kinetic profile of the excitatory glutamatergic synaptic protein expressions linked to N-methyl-D-aspartate receptor (NMDAR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and metabotropic glutamate receptor 5 (mGluR5) pathways in the prefrontal cortex of the VPA-exposed offspring at postnatal weeks 1, 2, and 4. Furthermore, VPA exposure showed a male-specific attenuation of the methyl-CpG-binding protein 2 (MeCP2) expressions both in the prefrontal cortex of offspring and in the gender-isolated neural progenitor cells (NPCs). In the gender-isolated NPCs culture, higher concentration of VPA induced an increased glutamatergic synaptic development along with decreased MeCP2 expression in both genders suggesting the role of MeCP2 in the modulation of synaptic development. In the small interfering RNA (siRNA) knock-down study, 50 pmol of Mecp2 siRNA inhibited the MeCP2 expression in male- but not in female-derived NPCs with concomitant induction of postsynaptic proteins such as PSD95. Taken together, we suggest that the male-inclined reduction of MeCP2 expression is involved in the abnormal development of glutamatergic synapse and male preponderance in the VPA animal models of ASD.
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In VPA-exposed rodents, fewer postsynaptic densities are observed in the hippocampus, whereas more and thicker postsynaptic densities are present in the medial PFC.
“Fewer postsynaptic densities are observed in the hippocampus of VPA exposed rodents [199], whereas more and thicker postsynaptic densities are present in the medial PFC [198].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [198]
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- Authors
- Kim, K. C., Choi, C. S., Kim, J.-W., Han, S.-H., Cheong, J. H., Ryu, J. H., & Shin, C. Y.
- Affiliations
- Konkuk University (KR)
- Sahmyook University (KR)
- Kyung Hee University (KR)
- Corresponding author
- Shin, Chan Young
- Venue
- Molecular Neurobiology
- Published
- 2014-11-18
- Volume
- 53
- Issue
- 1
- Pages
- 40-56
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- OpenAlex
- W1982456210
- Cited by
- 60
- References
- 97
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 3 · 2023: 5 · 2022: 6 · 2021: 2 · 2020: 6 · 2019: 7 · 2018: 6 · 2017: 5 · 2016: 6 · 2015: 4
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Molecular Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- MeCP2, sex differences, autism spectrum disorder, valproic acid, prenatal valproic acid exposure, glutamatergic synapses, NMDA receptor, AMPA receptors, mGluR5, prefrontal cortex, neural progenitor cells, epigenetic regulation, male preponderance, PSD-95
- MeSH terms
- Animals, Autistic Disorder, Behavior, Animal, Disease Models, Animal, Female, Pregnancy, Prenatal Exposure Delayed Effects, Sex Characteristics, Synapses, Valproic Acid, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Methyl-CpG-Binding Protein 2
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