UC Berkeley

mTORC1 is a central signaling hub that integrates intra- and extracellular signals to regulate a variety of cellular metabolic processes. Mutations in regulators of mTORC1 lead to neurodevelopmental disorders associated with autism, which is characterized by repetitive, inflexible behaviors. These behaviors likely result from alterations in striatal circuits that control motor learning and habit formation. However, the consequences of mTORC1 dysregulation on striatal neuron physiology are largely unknown. To investigate this, I deleted the mTORC1 negative regulator Tsc1 postnatally and prenatally from identified striatonigral and striatopallidal neurons and examined how cell autonomous upregulation of mTORC1 activity affects their morphology and physiology. I find that postnatal loss of Tsc1 increases the excitability of striatonigral, but not striatopallidal, neurons and selectively enhances corticostriatal synaptic transmission. I find that prenatal deletion of Tsc1 also enhances excitability of striatonigral, but not striatopallidal, neurons, and that this occurs through an increase in cortico-striatonigral synaptic transmission. I also observe that a loss of endocannabinoid-LTD drives enhanced cortical excitation of striatonigral neurons, and that this is associated with improved motor routine learning.

To investigate the molecular mechanism driving these synaptic changes, I performed translating ribosome affinity purification to determine gene expression changes in mice with loss of Tsc1 from either striatonigral or striatopallidal neurons. I find that Tsc1 deletion results in numerous translational differences in striatal neurons, and that many of these differences are specific to either striatonigral or striatopallidal neurons. Further, I extend my findings in the Tsc1 model to the Cntnap2-/- ASD mouse model, and find that corticostriatal transmission and motor routine learning are also enhanced by deletion of Cntnap2. These findings highlight the critical role of corticostriatal transmission in ASD mouse models, with implications for striatonigral pathway dysfunction in neuropsychiatric disease.