Thomas Schwarz, PhD
Professor of Neurology and Neurobiology
Harvard Medical School/Children’s Hospital
Department of Neurology (Neuroscience)

MRRC Project(s)

R01 GM42376
Structure, Localization and Cloning of Channels

R01 NS41062-01
Genetics of New Synaptic Components and Their Functions

P50 MH48108
Molecular and Cellular Signaling in Synaptic Plasticity - PI, Prj 4: Genetic Dissection of Transmitter Release

We study the functioning of the nervous and cardiovascular systems at the molecular and cellular level with a combination of molecular biological, electrophysiological, and genetic techniques. At present the lab has two foci: transmitter release and K+ channels.

K⁺ channels regulate the excitability of nerve cells and muscle cells and play a critical role in the electrical signaling of the brain. Because dozens of genes encoding these channels have been discovered to date, understanding the contribution of each individual gene to the overall physiology of the nervous system or other tissue has proven difficult. Neither pharmacological nor biophysical tools are sufficient for the task. Thus, though these channels are present throughout the development of the nervous system and are expressed in the mature brain in a complicated pattern of regional specificities, it is not yet known how significant an individual channel is for the development of appropriate connections, for the proper function of the nervous system, for the regulation of blood flow to the brain, or for the function of the heart.

The first project seeks to understand the significance of a K+ channel in both the cardiovascular and nervous systems. It specifically addresses the question of whether a craniofacial developmental defect (cleft palate) can be a secondary consequence of a primary defect in the signaling of the nervous system. In addition, because the proper homeostatic control of blood flow to the brain is necessary for supplying appropriate perfusion to regions of high activity, we seek to understand whether the IRK1 channel is critical to the signaling from neuron to blood vessel. Because changes in blood flow are essential for many brain-imaging techniques, this investigation has the additional potential benefit of revealing the physiological mechanism that underlies these vital methods in functional human neuroanatomy.

The secretion of neurotransmitter at a nerve terminal is a fundamental step in neuronal communication and understanding the regulation of that process will be essential for understanding synaptic plasticity and hence the fundamentals of learning, memory, and the activity dependent organization of the developing brain. Yet many fundamental questions remain concerning the mechanism of fusion, the targeting of synaptic vesicles, the control of exocytosis, the maintenance of the vesicle pool, and the mechanistic relationship of synaptic transmission to other forms of membrane trafficking. The second project uses Drosophila genetics to probe the mechanisms of the synapse. The synapse is vital to neuronal communication and changes in synapses are likely to be a major component of learning and memory. Defects in these processes are likely to lead to impaired cognitive function and, perhaps, a broad array of psychiatric disorders. Defects in the development of synaptic contacts may be a significant cause of mental retardation.

Changes in the strength of synaptic transmission figure prominently in many models of learning and memory. Some of this plasticity is accomplished by altering the release of neurotransmitters. Understanding the mechanisms of these changes will require a detailed knowledge of the workings of the nerve terminal and the regulated processes by which it secretes neurotransmitters. Many of the protein constituents of nerve terminals have been uncovered in recent years and in vitro studies have characterized the biochemical properties of these proteins. From these studies, models of the docking, fusion, and recycling of synaptic vesicles have been proposed. The third proposal consists of a set of genetic experiments in Drosophila that test the in vivo significance of two proteins in the synaptic vesicle membrane in the light of current models of membrane trafficking, and to uncover novel components of the synaptic apparatus. By studying genes important for synaptic function and development and by characterizing the consequences of mutations in this gene, we hope to uncover fundamental mechanisms of neurotransmission and gain insight into the pathological consequences of their malfunction.