Male-specific alteration in excitatory postsynaptic development and social interaction in prenatal valproic acid exposure model of autism spectrum disorder.
Department of Pharmacology, College of Pharmacy, Seoul National University, Seoul, Korea; Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University, Korea.
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 in 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 vGluT1 expression. Interestingly, despite of the similar increased expression of vGluT1, postsynaptic marker proteins such as PSD-95 and α-CAMKII expression was significantly elevated only in male offspring.
Electron microscopy showed increased number of postsynapse in male but not in female at 4weeks of age. These results might suggest that the altered glutamatergic neuronal differentiation leads to deranged postsynaptic maturation only in male offspring prenatally exposed to VPA.
Consistent with the increased postsynaptic 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