PROJECT SUMMARY / ABSTRACT
Tourette syndrome (TS) is a neurodevelopmental disorder with a strong genetic component, affecting 0.5-1%
of children. TS is characterized by multiple, recurring tics, which are a source of significant disability. The
clinical management of TS poses considerable challenges, partially because all available pharmacotherapies
are not specific to the pathogenic mechanisms, and thus have only limited efficacy and significant side effects.
Understanding the genetic basis of TS is an essential step to elucidate the causes of this disorder; however,
until recently, all available information was limited to rare genetic mutations sporadically associated with TS
pedigrees, and thus could not be generalized to most patients. Recently, however, evidence from large genetic
studies and the first gene-expression analyses of postmortem samples from TS-affected individuals has
revealed that protocadherins, a superfamily of proteins regulating cell-cell interactions, play a key role in TS
pathogenesis. In support of these findings, the largest whole-exome studies on de novo mutations in TS
recently identified the protocadherin-encoding gene CELSR3 as one of the first high-confidence TS risk genes.
This R21 proposal seeks to leverage these new discoveries and explore the mechanisms whereby CELSR3
deficiency predisposes to TS, using transgenic mouse models harboring a mutation of this gene.
In preliminary studies, we found that juvenile peripubertal male and female CELSR3 heterozygous mice exhibit
TS-like phenotypes, including tic-like stereotypies and sensorimotor gating deficits, in comparison with their
wild-type littermates. Furthermore, previous experiments showed that CELSR3 has a critical role in interneuron
migration and the organization of dopaminergic projections. Based on this background, we hypothesize that
partial CELSR3 deficiency leads to TS-related neurobehavioral deficits by impairing the histoarchitectural and
molecular organization of the striatum. To test this hypothesis, the two aims of this application will respectively:
1) chart the trajectory of the behavioral impairments of CELSR3 heterozygous mice; and 2) determine the
histoarchitectural and transcriptomic alterations of the striatum of these mutants.
The proposed exploratory studies will be the first to elucidate the role of protocadherins in TS ontogeny and
validate the first model of TS based on a high-risk vulnerability gene. These results are likely to lead to the
identification of novel pathogenic processes and specific molecular pathways involved in TS etiology. Our
results will lead to future larger studies aimed at the analysis of early neurodevelopmental causes of TS and
the design of novel specific pharmacotherapies with better efficacy, tolerability, and safety profiles.