A two-hit hypothesis for dystonia pathophysiology: Cerebello-thalamo-striatal dysfunction and connectivity in DYT1 mice

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ABSTRACT Dystonia is neurodevelopmental disease characterized by involuntary twisting movements. Effective dystonia treatments remain elusive because the dysfunctional circuit(s) that cause and perpetuate the motor abnormalities is largely uncharacterized. One limitation to advancing our understanding of dystonia pathophysiology and developing novel therapeutic strategies is the lack of etiologically based animal models that exhibit overt dystonia-like behaviors. We overcame this limitation by engineering a mouse model that exhibits robust motor abnormalities starting in juvenile development, following a disruption of the dystonia gene, TOR1A.TorsinA, the protein that is made from the TOR1A, is important during brain development for synaptogenesis and its loss results in abnormal functional connectivity. I will use our novel mouse model to investigate how a loss of torsinA function in brain motor circuits causes dystonia. I will test a new idea: that dystonia results from sequential insults. First, genetic mutations cause a small but critical group of neurons to make aberrant anatomical connections. Then, sustained circuit dysfunction reinforces abnormal movements. These studies are possible because of multiple uniquely designed “tools" my lab has created and the advanced brain imaging methods that have been developed at UT Southwestern, where the study will be performed. This proposal will also advance our understanding of dystonia by identifying the brain circuit changes required to propagate and suppress motor dysfunction. This understanding will inform future work aimed at developing effective therapies for dystonia.