Acute rapamycin rescues the hyperexcitable phenotype of accumbal medium spiny neurons in the valproic acid rat model of autism spectrum disorder. (September 2022)

• Record Type: Journal Article
• Authors: Iezzi, D.; Curti, L.; Ranieri, G.; Gerace, E.; Costa, A.; Ilari, A.; La Rocca, A.; Luceri, C.; D'Ambrosio, M.; Silvestri, L.; Scardigli, M.; Mannaioni, G.; Masi, A.
• Is Part Of: Pharmacological research. Volume 183(2022)
• Publication Date: 2022-09
• Subjects: Autism -- Valproic acid -- Rapamycin -- mTOR -- Patch clamp -- Transcriptomics; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106401
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: We previously demonstrated that prenatal exposure to valproic acid (VPA), an environmental model of autism spectrum disorder (ASD), leads to a hyperexcitable phenotype associated with downregulation of inward-rectifying potassium currents in nucleus accumbens (NAc) medium spiny neurons (MSNs) of adolescent rats. Aberrant mTOR pathway function has been associated with autistic-like phenotypes in multiple animal models, including gestational exposure to VPA. The purpose of this work was to probe the involvement of the mTOR pathway in VPA-induced alterations of striatal excitability. Adolescent male Wistar rats prenatally exposed to VPA were treated acutely with the mTOR inhibitor rapamycin and used for behavioral tests, ex vivo brain slice electrophysiology, single-neuron morphometric analysis, synaptic protein quantification and gene expression analysis in the NAc. We report that postnatal rapamycin ameliorates the social deficit and reverts the abnormal excitability, but not the inward-rectifying potassium current defect, of accumbal MSNs. Synaptic transmission and neuronal morphology were largely unaffected by prenatal VPA exposure or postnatal rapamycin treatment. Transcriptome analysis revealed extensive deregulation of genes implied in neurodevelopmental disorders and ionic mechanisms exerted by prenatal VPA, which was partially reverted by postnatal rapamycin. The results of this work support the existence of antagonistic interaction between mTOR and VPA-induced pathways on social behavior, neurophysiological phenotype and gene expression profile, thus prompting further investigation of the mTOR pathway in the quest for specific therapeutic targets in ASD. Graphical abstract: ga1 Highlights: Prenatal exposure to valproic acid leads to a hyperexcitable phenotype of nucleus accumbens medium spiny neurons. Acute postnatal rapamycin rescues the social deficit and the hyperexcitable phenotype of accumbal MSNs. Treatments have minor effects on strength of synaptic transmission, neuronal morphology and expression of synaptic proteins. Many individual transcripts and gene pathways are disregulated by prenatal exposure to valproic acid and restored by postnatal rapamycin.