Neurodevelopment of Tourette syndrome

Yale University, New Haven CT

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Abstract

Like other complex neuropsychiatric disorders, Tourette syndrome (TS) is thought to be a result of primary genetic/developmental abnormalities, long-term compensatory phenomena, and environmental factors. Despite having one of the highest familial recurrence rates among complex neuropsychiatric disorders, few gene variants achieving genome-wide statistical thresholds, and no definitive biomarker has emerged so far. Cortico-striatal- thalamo-cortical (CSTC) circuits have long been implicated in TS by neuroimaging studies, and postmortem analyses have suggested a decrease in number of striatal cholinergic and GABAergic interneurons in patients with severe, long-term TS. In the past funding period, we confirmed the decrease in interneurons by single nucleus RNA-seq (snRNA-seq) in the postmortem TS striatum. We also modeled human basal ganglia (BG) development in organoids with patient-derived induced pluripotent stem cells (iPSC) to understand the time of origin and potential developmental causes for the decrease in interneurons found in TS during adulthood. Basal ganglia organoids from TS individuals fail to generate normal numbers of striatal cholinergic and somatostatin/NPY GABAergic interneurons due to hypo-responsiveness to the sonic hedgehog (SHH) pathway, suggesting an early developmental origin for the mature interneuron deficit in the TS brain. In the proposed continuation of this research, in Aim 1 we will expand the postmortem snRNA-seq studies to additional regions of the CSTC circuits in a much larger number of subjects (n=50 TS and 50 controls), to fully understand the extent and the spread of the interneuron loss. In Aim 2, we will use BG organoids for parallel analyses of single cell transcriptome, enhancer activity and 3D chromatin conformation to reconstruct the gene regulatory programs that govern the development and maturation of BG cell types. We will then elucidate the alterations in transcription factor (TF) activity and BG gene regulatory network downstream from SHH that are potentially responsible for the deficiency in interneuron development in TS individuals. In Aim 3, we will use CRISPRa to overexpress in TS organoids TFs that are upstream positive regulators of interneuron development to establish whether this perturbation is sufficient to revert the loss of cholinergic and GABAergic interneurons back to control levels. In a final set of experiments (Aim 4), we will perform lineage analyses to identify the precise cellular mechanism of the interneuron loss in TS, i.e., whether there is a failure to allocate a sufficient number of interneuron founder cells, a failed expansion of interneuron precursor lineages during development, or both. These complementary experiments will define the time of origin, cellular and molecular pathophysiology of TS and provide a disease model that can be used in future translational studies.