Effects of Risperidone and Prenatal Poly I:C Exposure on GABAA Receptors and AKT-GSK3β Pathway in the Ventral Tegmental Area of Female Juvenile Rats

Shiyan Chen; Jiamei Lian; Yueqing Su; Chao Deng

doi:10.3390/biom12050732

Effects of Risperidone and Prenatal Poly I:C Exposure on GABA_A Receptors and AKT-GSK3β Pathway in the Ventral Tegmental Area of Female Juvenile Rats

Biomolecules. 2022 May 23;12(5):732. doi: 10.3390/biom12050732.

Authors

Shiyan Chen^{1

2

3}, Jiamei Lian^{2

3}, Yueqing Su^{2

3

4}, Chao Deng^{2

3}

Affiliations

¹ The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China.
² Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia.
³ School of Medical, Indigenous and Health Sciences and Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia.
⁴ Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynaecology and Paediatrics, Fujian Medical University, Fuzhou 350001, China.

Abstract

The ventral tegmental area (VTA) in the ventral midbrain is the origin of the dopaminergic neurotransmission pathways. Although GABA_A receptors and AKT-GSK3β signaling are involved in the pathophysiology of mental disorders and are modulated by antipsychotics, an unmet task is to reveal the pathological changes in these biomarkers and antipsychotic modulations in the VTA. Using a juvenile polyriboinosinic-polyribocytidylic acid (Poly I:C) psychiatric rat model, this study investigated the effects of adolescent risperidone treatment on GABA_A receptors and AKT/GSK3β in the VTA. Pregnant female Sprague-Dawley rats were administered Poly I:C (5mg/kg; i.p) or saline at gestational day 15. Juvenile female offspring received risperidone (0.9 mg/kg, twice per day) or a vehicle from postnatal day 35 for 25 days. Poly I:C offspring had significantly decreased mRNA expression of GABA_A receptor β3 subunits and glutamic acid decarboxylase (GAD2) in the VTA, while risperidone partially reversed the decreased GAD2 expression. Prenatal Poly I:C exposure led to increased expression of AKT2 and GSK3β. Risperidone decreased GABA_A receptor β2/3, but increased AKT2 mRNA expression in the VTA of healthy rats. This study suggests that Poly I:C-elicited maternal immune activation and risperidone differentially modulate GABAergic neurotransmission and AKT-GSK3β signaling in the VTA of adolescent rats.

Keywords: GABAA receptor; GSK3β; maternal immune activation; risperidone; ventral tegmental area.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antipsychotic Agents* / pharmacology
Female
Glycogen Synthase Kinase 3 beta / metabolism
Humans
Poly I-C / pharmacology
Pregnancy
Proto-Oncogene Proteins c-akt / metabolism
RNA, Messenger / metabolism
Rats
Rats, Sprague-Dawley
Receptors, GABA-A / genetics
Receptors, GABA-A / metabolism
Risperidone / metabolism
Risperidone / pharmacology
Ventral Tegmental Area* / metabolism
gamma-Aminobutyric Acid / metabolism

Substances

Antipsychotic Agents
RNA, Messenger
Receptors, GABA-A
gamma-Aminobutyric Acid
Glycogen Synthase Kinase 3 beta
Proto-Oncogene Proteins c-akt
Risperidone
Poly I-C

Grants and funding

This study was funded by the Australian National Health and Medical Research Council (NHMRC) Project Grant (APP 1104184) to C.D. and J.L.; J.L. was also supported by an NHMRC Early Career Fellowship Award (APP1125937). S.C. was supported by the Young Core Teacher Fund of Fujian Medical University (JGG201308). The funding bodies had no further role in the study design, decision to publish or preparation of the manuscript.