Mammalian Target of Rapamycin-RhoA Signaling Impairments in Direct Striatal Projection Neurons Induce Altered Behaviors and Striatal Physiology in Mice

Background: As an integrator of molecular pathways, mTOR (mammalian target of rapamycin) has been associated with diseases including neurodevelopmental, psychiatric, and neurodegenerative disorders such as autism spectrum disorder, 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.

Methods: Using Drd1-Cre mTOR-conditional knockout male mice, we combined behavioral, biochemical, electrophysiological, and morphological analysis aiming to untangle the role of mTOR in direct pathway striatal projection neurons and how this would impact on striatal physiology.

Results: Our results indicate deep behavioral changes in absence of mTOR in Drd1-expressing neurons such as decreased spontaneous locomotion, impaired social interaction, and decreased marble-burying behavior. These alterations were accompanied by a Kv1.1-induced increase in the fast phase of afterhyperpolarization and coincident decreased distal spine density in striatal direct pathway striatal projection neurons. The physiological changes were mechanistically independent of protein synthesis but sensitive to pharmacological blockade of transforming protein RhoA activity.

Conclusions: These results identify mTOR 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 monogenic disorders associated with the mTOR signaling pathway.