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

Scientists studied a mouse model of autism that has a genetic mutation similar to some people with autism. They found problems in a brain area called the dorsal striatum, which is important for movement and behavior. The mice showed autism-like behaviors and had disrupted communication between brain cells in this region. Specifically, certain brain receptors weren't working properly, which may explain some autism symptoms.

This research helps us understand how genetic changes can affect brain function in autism.

This study investigated synaptic dysfunction in the dorsal striatum of R451C-Neuroligin 3 knock-in mice, a model of autism spectrum disorder. Researchers used behavioral, proteomic, biochemical, and electrophysiological approaches to examine striatal function. The study confirmed striatum-dependent behavioral alterations and revealed significant impairments in corticostriatal long-term synaptic plasticity. Specifically, group I metabotropic glutamate receptor (mGluR) signaling was disrupted, with reduced type 5 mGluR protein expression at striatal synapses.

The mGluRs failed to potentiate NMDA receptor-mediated currents despite normal ionotropic receptor kinetics. These findings suggest that mGluR5 signaling dysfunction in the dorsal striatum contributes to autism-related behaviors in this mouse model, providing insights into potential synaptic mechanisms underlying ASD.

These findings suggest that mGluR5 signaling dysfunction in the dorsal striatum may contribute to autism-related behaviors. This research identifies potential therapeutic targets, as mGluR5 modulators could theoretically address some autism symptoms. However, translation from mouse models to human interventions requires significant additional research and clinical validation.

Sample size not reported. Study conducted in mouse model which may not fully translate to human autism. Single mutation model may not represent the heterogeneity of autism spectrum disorder. Behavioral details not specified in abstract.

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.