Striatal Cholinergic Interneuron Dysfunction in Dystonia Pathophysiology

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PROJECT SUMMARY DYT1 dystonia is the most common inherited form of dystonia, a common and disabling neurological movement disorder. Striatal dysfunction is thought to play a key role in dystonia pathophysiology, but it is unclear which neuronal classes are dysfunctional and drive abnormal movement. Morphologic and electrophysiologic abnormalities of striatal cholinergic interneurons (ChIs) have been observed in DYT1 mouse models, but many of these models do not exhibit motor dysfunction. This barrier to dystonia research was overcome when the Dauer lab generated an overtly symptomatic mouse model by conditionally knocking out torsinA from forebrain cholinergic and GABAergic neurons (including all striatal neurons) using Dlx5/6-Cre (“Dlx-CKO”). These mice exhibit dystonic-like twisting movements, selective degeneration of dorsal striatal ChIs, and morphologic and electrophysiologic changes in surviving ChIs. Clinically effective anti-muscarinic drugs suppress twisting movements in Dlx-CKO mice, establishing predictive validity and suggesting that aberrant function of remaining (non-degenerating) ChIs contributes to abnormal movement. To explore this possibility, I performed immunohistochemistry to determine intensity of phosphorylated ribosomal protein S6 (p-rpS6), a marker correlated with ChI activity. My preliminary data demonstrate that torsinA null ChIs exhibit elevated phosphorylated ribosomal protein S6 (p-rpS6), a finding consistent with altered ChI activity. Consistent with the hypothesis that abnormal activity of these cells contributes to dystonic-like movements, the p-rpS6 increase is selective to dorsal striatal (motor) ChIs and present only at behaviorally symptomatic ages. To examine whether abnormal ChI signaling is necessary for abnormal movement, I selectively lesioned these cells from the striatum of Dlx-CKO mice at symptomatic and pre-symptomatic ages and found that ChI ablation reverses and prevents abnormal twisting movements in Dlx-CKO mice, establishing their central role in dystonic-like symptoms. Based on my preliminary data and considerable published electrophysiological work implicating ChIs in dystonia pathophysiology, I hypothesize that ChIs are functionally abnormal in Dlx-CKO mice, and modulating ChI function is an effective therapeutic strategy. I will test this hypothesis with two aims: (1) defining the relationship between ChI activity and dystonic-like limb clasping using Designer Receptor Exclusively Activated by Designer Drugs (DREADD) technology and (2) determining if ChI-targeted genetic rescue of torsinA expression rescues neuropathologic and behavioral phenotypes in Dlx-CKO mice. The proposed studies will rigorously assess ChI dysfunction and therapeutic potential in one of the only overtly symptomatic rodent models of dystonia. Completion of the proposed work will further my writing, technical, and scientific skills and facilitate my development as a physician-scientist focused on neurologic disease.