# Neurodevelopment of Tourette syndrome

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $520,453

## Abstract

Tourette syndrome (TS) is a common disorder that afflicts as many as 1 in 150 children. Despite the high
familiar recurrence rate, no significant causative or predisposing factor has yet emerged in TS. Neuroimaging
and anatomical studies have implicated the striatum within the basal ganglia in TS. In postmortem brain tissue
of patients with severe TS we found a decrease in striatal cholinergic neurons (CH/TAN) and two types of
GABA interneurons, the parvalbumin+ (PV) and Somatostatin/Nitric Oxide Synthase /Neuropeptide Y+
(SST/NOS/NPY) by immunocytochemistry. Transcriptome profiling by RNA sequencing highlighted a
decrease in synaptic neurotransmission and metabolism-related biofunctions in TS, as well as a prominent
increase in inflammatory transcripts, as compared to matched normal controls (NC) brains. However, these
signatures are an average of a complex cellular mixture and most likely miss changes occurring in cell
subpopulations, particularly interneurons. We now seek to identify the transcriptome of striatal medium spiny
neuron (MSN), interneuron (INT), astrocytes & microglia (AST/MICR) and oligodendrocytes (OLIG) cell
subpopulations by fluorescence-activated nuclear sorting (FAN) as well as single neuronal nuclei in TS and NC
postmortem brain tissue. Correspondingly, the epigenome of these cell types will be characterized by
chromatin immunoprecipitation and sequencing (ChIP-seq) in the same cellular fractions. Differentially active
enhancer regions will be mapped in the striatum of TS vs NC and a gene regulatory network encompassing
changes in gene expression and corresponding enhancer activities will be built. Network modules differentially
active in TS will be used to construct a model of dysfunctional striatal circuitry in TS. To understand the origin
and potential causes of this network dysfunction, we will recapitulate early telencephalic development in vitro
using a human induced pluripotent stem cell (iPSC) model of the disorder. Basal ganglia and cortical
organoids from chronic TS patients, recovered TS patients and NC will be longitudinally analyzed and
compared on the cellular, transcriptomic, epigenomic and electrophysiological levels to reveal cell fate,
neuronal differentiation, molecular and functional abnormalities that underlie the disorder and its outcome.
These complementary experiments will define the likely time of origin, pathophysiology, and molecular
underpinnings of TS and provide a disease model where genetic and epigenetic changes can be perturbed to
assess their neurobiological effects.

## Key facts

- **NIH application ID:** 10063046
- **Project number:** 5R01MH118453-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** FLORA M VACCARINO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $520,453
- **Award type:** 5
- **Project period:** 2019-01-19 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10063046

## Citation

> US National Institutes of Health, RePORTER application 10063046, Neurodevelopment of Tourette syndrome (5R01MH118453-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10063046. Licensed CC0.

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