Impaired metabotropic glutamate type 5 receptor signaling in the dorsal striatum of the R451C-neuroligin 3 mouse model of Autism Spectrum Disorder

Background 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 gene. Methods We used behavioral, proteomic, biochemical, and electrophysiological approaches to explore the dorsal striatum-dependent functions in the R451C-neuroligin3 mouse model of ASD. Results A detailed behavioral analysis confirmed striatum-dependent alterations in these mice. We further explored the corticostriatal synaptic function, disclosing modifications of the glutamatergic postsynaptic density protein composition, which functionally result in the impairment of different forms of corticostriatal synaptic plasticity, namely activity-dependent long-term depression and potentiation, and group I metabotropic glutamate receptor-dependent synaptic depression. We also found reduced protein expression levels of type 5 metabotropic glutamate receptor at striatal synapses, which likely preclude the expression of long-term potentiation and depression by preventing the potentiation of NMDA receptor-mediated currents and a sufficient generation of endocannabinoids, respectively. Conclusions Overall, our findings point to a significant impairment of type 5 metabotropic glutamate receptor signaling, affecting the dorsal striatum function, which underlies specific autism-relevant behaviors in R451C-neuroligin3 mice.