UCLA

Tourette Syndrome (TS) is a genetic, neurodevelopmental disorder that is characterized by the juvenile-onset of chronic motor and vocal tics and is often associated with other overlapping neuropsychiatric comorbidities including OCD, ADHD, self-injurious behaviors (SIBs), and social impairments. In this dissertation, we report novel TS-like behaviors in a CNS-specific conditional knockout mouse model of Zfp521 (Zfp521-BrKO). Zfp521 is a zinc finger transcription factor first identified as enriched in striatonigral MSNs from our laboratory's FACS-array profiling of striatal MSN subtypes (and later verified by the BAC-TRAP methodology) and is known to be critical in the differentiation of ES cells into early neuronal precursors. Converging evidence from the striatal expression of Zfp521 and the neurodevelopmental roles of Zfp423 (paralog) and Ebf1 (a physically interacting transcriptional partner of Zfp521) suggests Zfp521 may be involved in striatal development. Extensive studies of the behavioral and neuropathological phenotypes show that Zfp521-BrKO mice demonstrate robust TS-like face validity, exhibiting juvenile-onset of several simple and complex tic-like motor behaviors that are exacerbated by stress or suppressed by attention, multiple TS-associated comorbidities, and select neuropathologies reported in TS patients. Pharmacological suppression of tic-like behaviors by haloperidol, a neuroleptic that is among the first-line treatments for TS, but not by fluoxetine, a SSRI used to treat OCD, reveals Zfp521-BrKO mice demonstrate selective predictive validity for tics associated with TS rather than the compulsive behaviors of OCD. Interestingly, Zfp521-BrKO mice are highly resistant to haloperidol-induced catalepsy, implicating hypofunctional indirect pathway D2-MSNs in the pathophysiology of the tic-like behaviors in the mutant mice, which was confirmed through immunohistochemical, electrophysiological, and optogenetic interrogation of the striatopallidal MSNs. Furthermore, supported by electrophysiological evidence of D1-MSN activation by haloperidol in Zfp521-BrKO, presumably by presynaptic D2-autoreceptor-mediated increase in DA release, we show that Zfp521-BrKO mice demonstrate unique predictive validity for tic-suppression by DA-agonism with pergolide and selective D1-receptor agonism. Our studies not only establish Zfp521-BrKO mice as a comprehensive animal model of TS with a distinct underlying BG circuitry dysfunction, but also highlights the potential of these mice as a powerful tool for TS drug discovery. Elucidating the molecular mechanisms of Zfp521, in both the normal and TS brain, will provide critical insights into the fundamental processes of striatal development and have significant implications for human genetic studies of TS.