Grant: Operating Grant

The autonomic nervous system consists of sympathetic and parasympathetic neurons collected in several ganglia throughout the body and most organs and tissues rely on the autonomic nervous system to regulate their function. The synapses in autonomic ganglia represent the final output of various CNS structures that regulate autonomic activity; if these synapses do not develop or function properly, this vital link between the CNS and the periphery is disrupted, and a wide range of abnormalities and unique syndromes ensue. These syndromes include abnormal heart rate that predisposes a person to life-threatening arrhythmias, gastrointestinal problems, poor bladder control, and erectile dysfunction. Collectively these symptoms and abnormalities are referred to as autonomic neuropathies or dysautonomias and adversely affect a person's quality of life and life expectancy. This proposal has two major goals. One is to understand how neural circuits in autonomic ganglia are established during development. Our overall hypothesis is that synapses that make the postsynaptic neuron fire are useful and become stabilized whereas those that cannot are inappropriate and are eliminated. To test this we will investigate different mouse models that have targeted mutations in genes that result in a disruption of either pre- or postsynaptic function. Our second goal is to understand how diseases disrupt the function of synapses in autonomic ganglia and produce dysautonomia. We showed recently that mild elevations in cytosolic reactive oxygen species (ROS) inactivate nAChRs on sympathetic neurons and produce a long-lasting depression in synaptic transmission in sympathetic ganglia. Elevated ROS have been implicated in a number of diseases, including diabetes, and recently, we showed that synaptic transmission in sympathetic ganglia is depressed in diabetic mice. We plan to determine how ROS disrupt the function of receptors at synapses in autonomic ganglia and produce dysautonomias.