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An alpha 5-GABA A receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in rats exposed to valproic acid in utero.
- Source :
-
Autism research : official journal of the International Society for Autism Research [Autism Res] 2024 Aug; Vol. 17 (8), pp. 1534-1544. Date of Electronic Publication: 2024 Jun 22. - Publication Year :
- 2024
-
Abstract
- Autism spectrum disorders (ASDs) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of α5-containing GABA <subscript>A</subscript> receptors (α5-GABA <subscript>A</subscript> Rs) SH-053-2'F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in rats exposed to valproic acid (VPA) in utero, an established risk factor for autism. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH-053-2'F-R-CH3 could attenuate these changes. SH-053-2'F-R-CH3 was administered intraperitoneally 30 min before each behavioral test and electrophysiology. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self-grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH-053-2'F-R-CH3 attenuated the impairments in sociability and cognitive function in male VPA-exposed rats without attenuating the decreased social interaction in females. Adult male and female VPA-exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH-053-2'F-R-CH3. Despite sex differences, our findings indicate that α5-GABA <subscript>A</subscript> Rs positive allosteric modulators may effectively attenuate some core ASD symptoms.<br /> (© 2024 International Society for Autism Research and Wiley Periodicals LLC.)
- Subjects :
- Animals
Female
Rats
Male
Pregnancy
Dopamine metabolism
Autism Spectrum Disorder chemically induced
Ventral Tegmental Area drug effects
Ventral Tegmental Area physiopathology
Rats, Sprague-Dawley
Allosteric Regulation drug effects
Disease Models, Animal
Behavior, Animal drug effects
Cognitive Dysfunction chemically induced
Cognitive Dysfunction physiopathology
Valproic Acid pharmacology
Prenatal Exposure Delayed Effects
Receptors, GABA-A drug effects
Social Behavior
Subjects
Details
- Language :
- English
- ISSN :
- 1939-3806
- Volume :
- 17
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Autism research : official journal of the International Society for Autism Research
- Publication Type :
- Academic Journal
- Accession number :
- 39169698
- Full Text :
- https://doi.org/10.1002/aur.3178