Impairment of Group I Metabotropic Glutamate Receptors in the Dorsal Striatum of the R451C-Neuroligin 3 Mouse Model of Autism Spectrum Disorder.

Human genetics indicates enrichment of synaptic pathway-related mutations in Autism Spectrum Disorder (ASD). Accordingly, several preclinical studies have reported synaptic alterations in different brain areas of relevant ASD mouse models. In particular, we previously showed that corticostriatal long-term synaptic depression is impaired in the dorsal striatum of mice carrying the ASD-associated R451C mutation in the neuroligin3 (NL3) gene, coding for the postsynaptic protein neuroligin 3. Here, we used behavioral, proteomic, biochemical, and electrophysiological approaches to explore the dorsal striatum-dependent functions in the R451C-NL3 knock-in mouse model of ASD. A detailed behavioral analysis confirmed striatum-dependent alterations in these mice. We further explored the synaptic function in the dorsal striatum, revealing modifications of the glutamatergic postsynaptic density protein composition and the impairment of different forms of corticostriatal long-term synaptic plasticity involving the activation of group I metabotropic glutamate receptors, namely activity-dependent depression and potentiation, and pharmacological 3,5-DHPG-induced synaptic depression. Notably, activation of group I metabotropic glutamate receptors was not able to potentiate NMDA receptor-mediated currents despite unaltered kinetics of the ionotropic receptors. Protein expression levels of type 5 metabotropic glutamate receptors were reduced at striatal synapses. Overall, our findings point to a significant impairment of metabotropic glutamate receptor type 5 signaling in NL3 knock-in mice, affecting the dorsal striatum circuitry, which is implicated in autism-related behaviors.