Transcriptome Analysis in Hippocampus of Rats Prenatally Exposed to Valproic Acid and Effects of Intranasal Treatment of Oxytocin

Abstract

Autism spectrum disorder (ASD) is a heterogeneous disorder characterized by repetitive behaviors and social impairments, often accompanied by learning disabilities. It has been documented that the neuropeptide oxytocin (OXT) ameliorates core symptoms in patients with ASD. We recently reported that chronic administration of intranasal OXT reversed social and learning impairments in prenatally valproic acid (VPA)-exposed rats. However, the underlying molecular mechanisms remain unclear. Here, we explored molecular alterations in the hippocampus of rats and the effects of chronic administration of intranasal OXT (12 μg/kg/d). Microarray analyses revealed that prenatal VPA exposure altered gene expression, a part of which is suggested as a candidate in ASD and is involved in key features including memory, developmental processes, and epilepsy. OXT partly improved the expression of these genes, which were predicted to interact with those involved in social behaviors and hippocampal-dependent memory. Collectively, the present study documented molecular profiling in the hippocampus related to ASD and improvement by chronic treatment with OXT.

Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder

“…In vivo , subcutaneous oxytocin injections induced upregulation of hippocampal postsynaptic proteins PSD95 and Nlgn3 of Shank3 deficient mice ( 251 ). In rats exposed to VPA prenatally, chronic intranasal oxytocin administration rescued ASD-like behaviors including learning and memory impairments ( 198 ), and enhanced the expression of multiple genes in the hippocampus linked to synaptic function, learning, memory, and neurodevelopment ( 252 ). Erythropoietin, a glycoprotein hormone, has recently been reported to inhibit the astrogliosis in the hippocampal CA1 subfield in both LPS ( 227 ) and VPA ( 266 ) induced rat models of ASD, contributing to the enhanced learning and memory task performance ( 227 ).…”

Intranasal Polymeric and Lipid-Based Nanocarriers for CNS Drug Delivery

“…Furthermore, intranasal oxytocin attenuated the cognitive deficits caused by Aβ [ 117 ]. Oxytocin has also been reported to alleviate the core symptoms of autism spectrum disorder (ASD) and when administered intranasally to adolescent animals that were prenatally exposed to valproic acid, ASD-like phenotypes were ameliorated at a gene expression level [ 118 ]. Intranasal oxytocin is also reported to have antipsychotic effects and has been trialled as an adjunctive therapy for schizophrenia.…”

Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism

“…Gene expression analyses of the brains of mice in the VPA and MIA models have been conducted using RNA microarray analysis or next-generation RNA sequencing (RNAseq). In the majority of those animal studies, the fetus was exposed to the drug during mid-gestation, but RNA expression was analyzed in adult animals, typically following behavioral testing (e.g., see Qian et al, 2018;Zhao et al, 2019;Matsuo et al, 2022;Zhang et al, 2018). This approach has the potential to explain behavior in terms of contemporaneous gene expression but does not inform as to the initial molecular events occurring at the time the environmental stressor is present.…”