Modulation of Transmitter Release

University Of California-Berkeley, Berkeley CA

Investigators

Abstract

Lay Summary NSF Grant 0413936 Neural and Glial Mechanisms Program Division of Integrative Biology and Neuroscience Directorate for Biological Sciences Synapses are the points of information transfer between neurons and their targets. Synaptic transmission is regulated by neuromodulators and prior activity. This synaptic modifiability greatly increases the complexity of information processing at synapses, it underlies the adaptability of the nervous system to changing circumstances, and it is responsible for its ability to learn. Crayfish neuromuscular junctions (NMJs) are used to study the effects of prior activity and extrinsic modulation. This preparation offers many advantages, including ready availability and minimal cost, easy preparation, and suitability for electrophysiological recording, and physiological and biochemical properties identical to those of mammalian brain synapses Serotonin is a circulating hormone that regulates the amount of the chemical transmitter (glutamate) released by motor nerve terminals when they are electrically active. The biochemical pathways involved in serotonergic regulation will be explored. In particular, the project will test the hypothesis suggested by preliminary evidence that serotonin operates in part by causing the production of cyclic adenosine 3',5'-monophosphate, which in turn activates an enzyme called exchange protein activated by cyclic AMP (Epac) to modify vesicular proteins involved in making synaptic vesicles containing glutamate available for release. Normally cyclic AMP must also activate another protein (hyperpolarization and cyclic nucleotide-activated ion channels or HCNCs) to enhance transmission, but following extensive electrical activity, HCNCs are not needed for serotonin to have an effect. The hypothesis that under these circumstances serotonin acts only via the Epac pathway will be tested. It is also planned to extend these experiments to fruit fly (Drosophila), because this would allow genetic manipulations not feasible with crayfish. A final aim of this project is to understand the mechanisms responsible for differences between phasic motor neurons, which are very effective in releasing a lot of glutamate to single action potentials, versus tonic synapses, which are unresponsive to single action potentials but show tremendous synaptic facilitation in releasing glutamate to a train of action potentials. Biophysical experiments using photosensitive chemical probes of molecular function ("caged calcium" chelators) will be used to distinguish these synapses. The project will involve training junior scientists for future careers in teaching and research, with an emphasis on recruiting women and minority participants as has been done in the past.