Striatal Cholinergic Interneuron Ablation Dystonia Model

Dystonias are a family of neurological movement disorders characterized by involuntary muscle contractions that cause abnormal repetitive twisting movements or postures. These symptoms can manifest in specific body regions or affect the entire body. As such, dystonias significantly hinder normal movement and can be debilitating. The precise causes of dystonia are unclear, and as such there are no curative therapies for the disease. Current research indicates that the basal ganglia, a region of the brain important for processing movement, is dysfunctional in dystonia; however, the neurological causes of this remain unknown. This is due, in part, to the lack of animal models that mimic most cases of dystonia. Accurate animal models are important for scientific research, as they allow us to manipulate and study the brain in ways not possible with humans. Our proposal seeks to develop model of dystonia by inducing the loss of a group of neurons, known as cholinergic interneurons, that are important for basal ganglia function. We hypothesize that the loss of a subset of these neurons will change the function of the surviving neurons such that they reorganize improperly and are unable to correctly regulate movement.

To develop this model, we will use a novel genetic approach to specifically kill cholinergic interneurons in mice. We will target these neurons at different ages and test whether depletion of cholinergic interneurons causes behaviors resembling dystonia. We will also study how the cellular function of the surviving neurons change by measuring properties that are important to their normal activity, such as cell excitability and morphology.

The results of our study will directly contribute to our understanding the neurological abnormalities that cause dystonia symptoms. Importantly, the model will form the basis for future studies that allow us to identify new targets and test new therapeutic interventions. This will be an invaluable tool for the development of new treatments for dystonia.