Postweaning positive modulation of α5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner.

Autor: Santrač A; Department of Pharmacology, University of Belgrade - Faculty of Pharmacy, Belgrade, Serbia., Bijelić D; Centre for Laser Microscopy, Institute of Physiology and Biochemistry 'Jean Giaja', University of Belgrade - Faculty of Biology, Belgrade, Serbia., Stevanović V; Department of Pharmacology, University of Belgrade - Faculty of Pharmacy, Belgrade, Serbia., Banićević M; Department of Pharmacology, University of Belgrade - Faculty of Pharmacy, Belgrade, Serbia.; Institute of Pharmacy and Molecular Biotechnology, Bioinformatics and Functional Genomics, Ruprecht-Karls University Heidelberg, Heidelberg, Germany., Aranđelović J; Department of Pharmacology, University of Belgrade - Faculty of Pharmacy, Belgrade, Serbia., Batinić B; Department of Physiology, University of Belgrade - Faculty of Pharmacy, Belgrade, Serbia., Sharmin D; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee and the Milwaukee Institute of Drug Discovery, Milwaukee, Wisconsin, USA., Cook JM; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee and the Milwaukee Institute of Drug Discovery, Milwaukee, Wisconsin, USA., Savić MM; Department of Pharmacology, University of Belgrade - Faculty of Pharmacy, Belgrade, Serbia.
Jazyk: angličtina
Zdroj: Autism research : official journal of the International Society for Autism Research [Autism Res] 2022 May; Vol. 15 (5), pp. 806-820. Date of Electronic Publication: 2022 Mar 10.
DOI: 10.1002/aur.2699
Abstrakt: Autism spectrum disorder (ASD), as a common neurodevelopmental disorder that encompasses impairments in social communication and interaction, as well as repetitive and restrictive behavior, still awaits an effective treatment strategy. The involvement of GABAergic neurotransmission, and especially a deficit of GABA A receptors that contain the α5 subunits, were implicated in pathogenesis of ASD. Therefore, we tested MP-III-022, a positive allosteric modulator (PAM) selective for α5GABAA receptors, in Wistar rats prenatally exposed to valproic acid, as an animal model useful for studying ASD. Postweaning rats of both sexes were treated for 7 days with vehicle or MP-III-022 at two doses pharmacokinetically determined as selective, and thereafter tested in a behavioral battery (social interaction test, elevated plus maze, spontaneous locomotor activity, and standard and reverse Morris water maze). Additional rats were used for establishing a primary neuronal culture and performing calcium imaging, and determination of hippocampal mRNA levels of GABRA5, NKCC1, and KCC2. MP-III-022 prevented impairments in many parameters connected with social, repetitive and restrictive behavioral domains. The lower and higher dose was more effective in males and females, respectively. Intriguingly, MP-III-022 elicited certain changes in control animals similar to those manifested in valproate animals themselves. Behavioral results were mirrored in GABA switch and spontaneous neuronal activity, assessed with calcium imaging, and also in expression changes of three genes analyzed. Our data support a role of α5GABAA receptors in pathophysiology of ASD, and suggest a potential application of selective PAMs in its treatment, that needs to be researched in a sex-specific manner. LAY SUMMARY: In rats prenatally exposed to valproate as a model of autism, a modulator of α5GABAA receptors ameliorated social, repetitive and restrictive impairments, and, intriguingly, elicited certain autism-like changes in control rats. Behavioral results were mirrored in GABA switch and spontaneous neuronal activity, and partly in gene expression changes. This shows a role of α5GABAA receptors in pathophysiology of ASD, and a potential application of their selective modulators in its treatment.
(© 2022 International Society for Autism Research and Wiley Periodicals LLC.)
Databáze: MEDLINE
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