Control of movement: Regulation of Excitatory and Inhibitory balance in hindbrain circuits

Patients diagnosed with schizophrenia have movement disruptions linked to defects in cerebellar function. These include changes in posture, balance, and stride length. Given this, some have proposed that gait could be used as a useful indicator to identify individuals at risk, prior to their first psychotic event. In addition, drug naive patients have dysregulated nitric oxide signaling, which plays an important role in modulation of CNS circuit function. Despite these findings, the underlying mechanism contributing to the gait and balance defects remains unknown. Our groups have had a long-standing interest in the role interneurons play in coordinating neuronal circuits to control gait. Interneurons function to balance excitatory and inhibitory singling in neuronal circuits, and disruption of this balance affects the coordinated outputs from circuits to affect behaviours such as walking. Given the link between gait and schizophrenia we are interested in characterizing the underlying mechanism(s) that contribute to these gait disturbances. Genetic studies of patients diagnosed with schizophrenia reveal that an enzyme known as neuronal nitric oxide synthase, which is involved in the synthesis of nitric oxide, is dysregulated. Interestingly, we have identified that nitric oxide functions in interneurons of the cerebellar cortex to strengthening inhibitory synapses. To better understand the underlying mechanism(s) of this, we identified a nitric oxide binding protein which when deleted specifically in cerebellar interneurons leads to gait defects. This project will address how cerebellar interneurons, and nitric oxide signaling, contribute to the development of circuits that control gait. Further, this work will provide us with key insights into potential therapeutics to regulate nitric oxide localization and function.