Regulation and modulation of presynaptic ion channels and transmitter release in healthy and diseased synapses.
Our research program focuses on studying mechanisms that control synaptic plasticity in the nervous system. We use several model systems that provide the opportunity to study these mechanisms directly. In particular, we are interested in those events that occur in nerve terminals to regulate or modulate synaptic transmission in both normal and disease conditions.
Electrical measurements of transmitter release and calcium imaging in nerve terminals: We use microelectrode recordings of transmitter release, in combination with high-resolution calcium imaging in adult motor nerve terminals to examine the characteristics and modulation of the calcium entry that control transmitter release at the synapse. We have developed a method for imaging the spatial distribution of calcium entry following a single action potential stimulus. Using this approach, we have provided evidence that a very small subset of the available calcium channels opens in the nerve terminal with each stimulus. We hypothesize that transmitter release is triggered by the opening of single calcium channels in these nerve terminals and have begun to study the modulation of this process. We are interested in the mechanisms that control calcium entry and how this entry triggers transmitter release. Calcium imaging experiments are combined with microelectrode recordings of the magnitude of transmitter release, and MCell computer models of ion diffusion and binding reactions within the nerve terminal, to aid in the interpretation of data collected.
Transmitter release in control and disease model mouse motor nerve terminals: We have been using mouse neuromuscular preparations to study the regulation of transmitter release in both normal mice, and those that have been passively-transferred the disease Lambert-Eaton Myasthenic syndrome. In addition, we also use con-focal imaging of neuromuscular junctions stained with various antibodies directed against presynaptic proteins to characterize the presence and distribution of relevant molecules. This work furthers our understanding of calcium-dependent mechanisms, and is part of our effort to evaluate the effects of novel calcium channel agonists that might be of therapeutic benefit in diseases that result in neuromuscular weakness.
Modulation of N- and P/Q-type calcium channels expressed in cell lines: We use cell lines expressing various calcium channel subtypes as a model system to examine directly the gating and modulation of these channels, and the effects of various novel drugs that we are developing. This allows us to study various forms of modulation in a model system where there are no other calcium channels expressed, and we can focus on studying in isolation the types of calcium channels that control transmitter release at many synapses.
Tarr, T.B., Dittrich, M., and Meriney, S.D. Are Unreliable Release Mechanisms Conserved from NMJ to CNS? Trends in Neuroscience 36: 14-22, 2013.
Meriney, S.D., and Dittrich, M. Organization and function of transmitter release sites at the neuromuscular junction. J. Physiology, 2013 (in press).
Dittrich, M., Pattillo, J.M., King, J.D., Cho, S., Stiles, J.R., and Meriney, S.D. An Excess Calcium Binding Site Model Predicts Neurotransmitter Release at the NMJ. Biophysical J., 2013 (in press).
Tarr, T.B., Malick, W., Liang, M., Valdomir, G., Frasso, M., Lacomis, D., Reddel, S.W., Garcia-Ocano, A., Wipf, P., and Meriney, S.D. Evaluation of a novel calcium channel agonist for therapeutic potential in Lambert-Eaton Myasthenic Syndrome. J. Neuroscience, 2013 (in press)
Liang, M. Tarr, T.B., Bravo-Altamirano, K., Valdomir, G., Rensch, G., Swanson, L., DeStefino, N.R., Mazzarisi, C.M. Olszewski, R.A. Wilson, G.M., Meriney, S.D. and Wipf P. Synthesis and Biological Evaluation of a Selective N- and P/Q-Type Calcium Channel Agonist. ACS Med. Chem. Lett. 3: 985-990, 2012.
Tarr ,T.B., Valdomir, G., Liang, M., Wipf, P., and Meriney, S.D. New calcium channel agonists as potential therapeutics in LEMS and other neuromuscular diseases. Annals N.Y. Acad. Sci. 1275: 85-91., 2012
Luo, F., Dittrich, M., Stiles, J.R., and Meriney, S.D. Single pixel optical fluctuation analysis of calcium channel function in active zones of motor nerve terminals. Journal of Neuroscience 31: 11268-11281, 2011.
Douthitt, H.L., Luo, F., McCann, S.D. and Meriney, S.D. Dynasore, an inhibitor of dynamin, increases the probability of transmitter release. Neuroscience 172: 187-195, 2011.
DeStefino, N.R., Pilato, A.A., Dittrich, M., Cherry, S.V., Cho, S., Joel, R.. Stiles, J.R. and Meriney, S.D. (R)-Roscovitine prolongs the mean open time of unitary N-type calcium channel currents. Neuroscience 167: 838-849, 2010.