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

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder that often presents with psychiatric conditions, including autism spectrum disorder (ASD). ASD is characterized by restricted, repetitive, and inflexible behaviors, which may result from abnormal activity in striatal circuits that mediate motor learning and action selection. To test whether altered striatal activity contributes to aberrant motor behaviors in the context of TSC, we conditionally deleted Tsc1 from direct or indirect pathway striatal projection neurons (dSPNs or iSPNs, respectively). We find that dSPN-specific loss of Tsc1 impairs endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses and strongly enhances corticostriatal synaptic drive, which is not observed in iSPNs. dSPN-Tsc1 KO, but not iSPN-Tsc1 KO, mice show enhanced motor learning, a phenotype observed in several mouse models of ASD. These findings demonstrate that dSPNs are particularly sensitive to Tsc1 loss and suggest that enhanced corticostriatal activation may contribute to altered motor behaviors in TSC.