Impaired metabotropic glutamate type 5 receptor signaling 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 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, disclosing 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. Protein expression levels of type 5 metabotropic glutamate receptor were reduced at striatal synapses, whereas the protein level and function of glutamate ionotropic receptors were unaltered. Overall, our findings point to a significant impairment of metabotropic glutamate receptor type 5 signaling in neuroligin 3 knock-in mice, affecting the dorsal striatum circuitry, that has been implicated in several autism-related behaviors.