Tuberous sclerosis complex (TSC) is a genetic disease with severe neurologic and psychiatric manifestations including epilepsy, developmental delay, and autism. Despite much progress in defining abnormal signaling pathways including the contribution of increased mTORC1 signaling, specific abnormalities that underlie the severe neurologic features in TSC remain poorly understood. We hypothesized that epilepsy and autism in TSC result from abnormalities of γ-aminobutyric acidergic (GABAergic) interneurons. To test this hypothesis, we generated conditional knockout mice with selective deletion of the Tsc1 gene in GABAergic interneuron progenitor cells. These interneuron-specific Tsc1 conditional knockout (CKO) mice have impaired growth and decreased survival. Cortical and hippocampal GABAergic interneurons of CKO mice are enlarged and show increased mTORC1 signaling. Total numbers of GABAergic cells are reduced in the cortex with differential reduction of specific GABAergic subtypes. Ectopic clusters of cells with increased mTORC1 signaling are also seen suggesting impaired interneuron migration. The functional consequences of these cellular changes are evident in the decreased seizure threshold on exposure to the proconvulsant flurothyl. These findings support an important role for the Tsc1 gene during GABAergic interneuron development, function, and possibly migration.

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Deep brain stimulation (DBS) is an established intervention for use in pediatric movement disorders, especially dystonia. Although multiple publications have provided guidelines for deep brain stimulation patient selection and programming in adults, there are no evidence-based or consensus statements published for pediatrics. The result is lack of standardized care and underutilization of this effective treatment. To this end, we assembled a focus group of 13 pediatric movement disorder specialists and 1 neurosurgeon experienced in pediatric deep brain stimulation to review recent literature and current practices and propose a standardized approach to candidate selection, implantation target site selection, and programming algorithms. For pediatric dystonia, we provide algorithms for (1) programming for initial session and follow-up sessions, and (2) troubleshooting side effects encountered during programming. We discuss common side effects, how they present, and recommendations for management. This topical review serves as a resource for movement disorders specialists interested in using deep brain stimulation for pediatric dystonia.