Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder in which patients frequently present with autism spectrum disorder (ASD). A core diagnostic criterion for ASD is the presence of restricted, repetitive behaviors, which may result from abnormal activity in striatal circuits that mediate motor learning, action selection and habit formation. Striatal control over motor behavior relies on the coordinated activity of two subtypes of principle neurons, direct pathway and indirect pathway spiny projection neurons (dSPNs or iSPNs, respectively), which provide the main output of the striatum. To test if altered striatal activity is sufficient to cause changes to motor behavior in the context of TSC, we conditionally deleted Tsc1 from dSPNs or iSPNs in mice and determined the consequences on synaptic function and motor learning. We find that mice with loss of Tsc1 from dSPNs, but not iSPNs, have enhanced motor routine learning in the accelerating rotarod task. In addition, dSPN Tsc1 KO mice have impaired endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses in the dorsal striatum. Consistent with a loss of eCB-LTD, disruption of Tsc1 in dSPNs, but not iSPNs, results in a strong enhancement of corticostriatal synaptic drive. Together these findings demonstrate that within the striatum, dSPNs show selective sensitivity to Tsc1 loss and indicate that enhanced cortical activation of the striatal direct pathway is a potential contributor to altered motor behaviors in TSC.