The Impact of Neonatal Hypoxia on the Transcriptional Regulation of Basal Ganglia Development

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Alabama
Investigators Name
Cowell, Rita, PhD

A loss of striatal parvalbumin (PV)-positive fast-spiking interneurons has been reported in Tourette Syndrome (TS). The appropriate maturation of these cells is required for the synchronization of striatal medium spiny neurons, and it has been proposed that a loss of these cells or alteration in function gives rise to aberrant activity of medium spiny neurons, premonitory urges, and motor tics. Our lab has identified a transcriptional regulator critical for the developmental induction of PV called PGC-1? (peroxisome proliferator activated receptor ? coactivator 1?). Interestingly, recent evidence suggests that decreases in PGC-1? expression and activity contribute to the development of Huntington Disease. However, PGC-1? knockout mice show profound motor coordination deficits by 4 weeks of age, suggesting a dependence on PGC-1? for the proper development of motor circuitry. Furthermore, it has been hypothesized that PV-positive neurons are vulnerable to neonatal hypoxia, and hypoxia has been associated with increased tic severity. PGC-1? could serve as a link between hypoxia and PV-positive neuron dysfunction, as PGC-1? activity is influenced by hypoxia. Therefore, we will determine the impact of developmental alterations in PGC-1? on gene expression in the basal ganglia and on motor behavior. Specifically, we will characterize the motor phenotype throughout the first 4 weeks of life, including ambulation (open field activity), vocalization (ultrasonic), and observation of stereotypies (video observation of grooming behavior) in mice with a loss or overexpression of PGC-1?. These experiments will reveal whether mice lacking PGC-1? can be used to understand the cellular abnormalities underlying TS. Then, we will determine whether early postnatal hypoxia is able to influence impair motor function by altering PGC-1?-dependent gene expression and interneuron function. Together, these studies will give insight as to how changes in PV and environmental/genetic factors converge to produce the debilitating motor symptoms in TS. Rita Cowell, Ph.D University of Alabama at Birmingham, Birmingham, AL Award: $150,000 Tourette Association of America Inc. – Research Grant Award 2012-2013