mTOR-RhoA signalling impairments in direct striatal projection neurons induce altered behaviours and striatal physiology in mice

As an integrator of molecular pathways, mTOR has been associated with diseases including neurodevelopmental, psychiatric and neurodegenerative disorders as autism, schizophrenia, and Huntington’s disease. An important brain area involved in all these diseases is the striatum. However, the mechanisms behind how mTOR is involved in striatal physiology and its relative role in distinct neuronal populations in these striatal-related diseases still remain to be clarified. Taking advantage of the D 1 -mTOR KO mice (males), we combined behavioural, biochemical, electrophysiological and morphological analysis aiming to untangle the role of mTOR in direct pathway striatal projection neurons (dMSNs) and how this would impact on striatal physiology. Our results indicate deep behavioural changes in absence of mTOR in dMSNs such as decreased spontaneous locomotion, impaired social interaction and repetitive behaviour. These were accompanied by a Kv1.1-induced increase in the fast phase of afterhyperpolarization and decreased distal spines density that were mechanistically independent of protein synthesis but dependent of RhoA activity. These results identify mTOR RhoA signaling as an important regulator of striatal functions through an intricate mechanism involving RhoA and culminating in Kv1.1 overfunction, which could be targeted to treat striatal-related mTORopathies.