Group I and group II metabotropic glutamate receptors are upregulated in the synapses of infant rats prenatally exposed to valproic acid

• Published in: Psychopharmacology 2023-12, Vol.240 (12), p.2617-2629
• Main Authors: D’Antoni, Simona, Schiavi, Sara, Buzzelli, Valeria, Giuffrida, Samuele, Feo, Alessandro, Ascone, Fabrizio, Busceti, Carla Letizia, Nicoletti, Ferdinando, Trezza, Viviana, Catania, Maria Vincenza
• Format: Article
• Language: English
• Subjects: Adolescent; Animals; Autism; Autism Spectrum Disorder - chemically induced; Autism Spectrum Disorder - drug therapy; Behavior, Animal; Biomedical and Life Sciences; Biomedicine; Disease Models, Animal; Divalproex; Female; Forebrain; Genetic aspects; Glutamic acid receptors (metabotropic); Health aspects; Humans; Infants; Neurodevelopmental disorders; Neurosciences; Neurotransmitter receptors; Original Investigation; Pharmacology/Toxicology; Phenotypes; Physiological aspects; Pregnancy; Prenatal drug exposure; Prenatal experience; Prenatal exposure; Prenatal Exposure Delayed Effects - chemically induced; Psychiatry; Rats; Receptors, Metabotropic Glutamate; Risk factors; Social Behavior; Stereotyped behavior; Synapses; Synaptosomes; Valproic acid; Valproic Acid - adverse effects; Western blotting
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-023-06457-w

Rationale Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and restricted/stereotyped behavior. Prenatal exposure to valproic acid (VPA) is associated with an increased risk of developing ASD in humans and autistic-like behaviors in rodents. Increasing evidence indicates that dysfunctions of glutamate receptors at synapses are associated with ASD. In the VPA rat model, an involvement of glutamate receptors in autism-like phenotypes has been suggested; however, few studies were carried out on metabotropic glutamate (mGlu) receptors. Objectives We examined the protein expression levels of group I (mGlu1 and mGlu5) and group II (mGlu2/3) mGlu receptors in rats prenatally exposed to VPA and evaluated the effect of mGlu receptor modulation on an early autism-like phenotype in these animals. Methods We used western blotting analysis on synaptosomes obtained from forebrain of control and VPA rats at different ages (postnatal day P13, 35, 90) and carried out ultrasonic vocalization (USV) emission test in infant control and VPA rats. Results The expression levels of all these receptors were significantly increased in infant VPA rats. No changes were detected in adolescent and adult rats. An acute treatment with the preferential mGlu2/3 antagonist, LY341495, attenuated the impairment in the USV emission in VPA rats. No effect was observed after a treatment with the mGlu5 selective antagonist, MTEP. Conclusions Our findings demonstrate that the expression of group I and group II mGlu receptors is upregulated at synapses of infant VPA rats and suggest that mGlu2/3 receptor modulation may have a therapeutic potential in ASD.