INVESTIGATING THE ROLE OF MGLU4 RECEPTOR IN CONTROLLING AUTISM-SENSITIVE BEHAVIORS IN MICE

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders with high heterogeneity and heritability, whose diagnostic is reached in presence of impaired social skills together with a restricted, repetitive repertoire of behaviors, interests and activities (DSM 5). Approved pharmacological treatments mostly target frequent neurobehavioral comorbidities and fail to relieve core social symptoms. Converging evidence from animal models and clinical studies suggest that behavioral alterations in ASD arise from dysfunction of striatal circuits, notably from excessive activity of D2 dopamine receptor-expressing striatal projection neurons (D2-SPNs) in the nucleus accumbens (NAc), a key structure involved in social reward processing (Le Merrer et al. 2024). Facilitating the activity of the glutamate mGlu4 receptor allows to put a brake on D2-SPNs and relieves ASD-like behaviors in several mouse models of ASD, highlighting the therapeutic interest of this receptor for ASD treatment. The purpose of the present study was to investigate the role of mGlu4 in controlling ASD-sensitive behaviors, either by exploring the consequences of full Grm4 gene deletion or by knocking down Grm4 expression in discrete brain regions of the reward/social circuit, namely in the NAc, dorsal striatum and medio-dorsal thalamus. We demonstrate that mGlu4 is a critical modulator of social behavior, most notably in the NAc.