Male‐specific alteration in excitatory post‐synaptic development and social interaction in pre‐natal valproic acid exposure model of autism spectrum disorder
Abstract
Autism spectrum disorder (ASD) is a pervasive developmental disorder characterized by three main behavioral symptoms including social deficits, impaired communication, and stereotyped and repetitive behaviors. ASD prevalence shows gender bias to male. Prenatal exposure to valproic acid (VPA), a drug used in epilepsy and bipolar disorder, induces autistic symptoms in both human and rodents. As we reported previously, prenatally VPA‐exposed animals at E12 showed impairment in social behavior without any overt reproductive toxicity. Social interactions were not significantly different between male and female rats in control condition. However, VPA‐exposed male offspring showed significantly impaired social interaction while female offspring showed only marginal deficits in social interaction. Similar male inclination was observed in hyperactivity behavior induced by VPA. In addition to the ASD‐like behavioral phenotype, prenatally VPA‐exposed rat offspring shows crooked tail phenotype, which was not different between male and female groups. Both male and female rat showed reduced GABAergic neuronal marker GAD and increased glutamatergic neuronal marker vG luT1 expression. Interestingly, despite of the similar increased expression of vG luT1, post‐synaptic marker proteins such as PSD‐95 and α‐CAMKII expression was significantly elevated only in male offspring. Electron microscopy showed increased number of post‐synapse in male but not in female at 4 weeks of age. These results might suggest that the altered glutamatergic neuronal differentiation leads to deranged post‐synaptic maturation only in male offspring prenatally exposed to VPA. Consistent with the increased post‐synaptic compartment, VPA‐exposed male rats showed higher sensitivity to electric shock than VPA‐exposed female rats. These results suggest that prenatally VPA‐exposed rats show the male preponderance of ASD‐like behaviors including defective social interaction similar to human autistic patients, which might be caused by ectopic increase in glutamatergic synapses in male rats.
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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 [199]
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- Authors
- Kim, K. C., Kim, P., Go, H. S., Choi, C. S., Park, J. H., Kim, H. J., Jeon, S. J., dela Pena, I. C., Han, S., Cheong, J. H., Ryu, J. H., & Shin, C. Y.
- Affiliations
- Seoul National University (KR)
- Konkuk University (KR)
- Sahmyook University (KR)
- University of California, Los Angeles (US)
- Department of Pharmacy Sahmyook University Seoul Korea
- Kyung Hee University (KR)
- Corresponding author
- Shin, Chan Young
- ORCID
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2013-02-03
- Volume
- 124
- Issue
- 6
- Pages
- 832-843
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1984368478
- Cited by
- 212
- References
- 71
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 18 · 2023: 15 · 2022: 18 · 2021: 22 · 2020: 19 · 2019: 13 · 2018: 18 · 2017: 15 · 2016: 18 · 2015: 10 · 2014: 8 · 2013: 14 · 2012: 1
- FWCI
- 9.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mid-career Researcher Program (2011-0014258)
- Framework of International Cooperation Program (2012K2A1A2032549)
- National Research Foundation of Korea
- Korea government
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- autism spectrum disorder, valproic acid, prenatal drug exposure, sex differences, social interaction deficits, glutamatergic neurons, VGLUT1, GABAergic neurons, GAD, PSD-95, CaMKIIα, synapse number, hyperactivity
- MeSH terms
- Animals, Child, Child Development Disorders, Pervasive, Disease Models, Animal, Female, Humans, Interpersonal Relations, Male, Pregnancy, Prenatal Exposure Delayed Effects, Random Allocation, Sex Characteristics, Synapses, Valproic Acid, Rats, Sprague-Dawley, Rats, Synaptic Potentials
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