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 neuromuscular 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 controls 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 use mouse neuromuscular preparations to study the regulation of transmitter release in both normal mice, and neuromuscular disease models (including Lambert-Eaton Myasthenic syndrome and Spinal Muscular Atrophy). 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. This work includes generation of chimeric channels and mutagenesis of Cav2 channel proteins to evaluate channel structure-function relationships.
The development of novel drugs to treat neuromuscular disease: We collaborate with Dr. Peter Wipf in the Chemistry Department to develop new analogs of (R)-roscovitine that are selective Cav2 calcium channel agonist gating modifiers (and lack cyclin dependent kinase activity). In particular, we have developed GV-58 which we have shown can reverse neuromuscular weakness in mouse models of Lambert-Eaton myasthenic syndrome and Spinal Muscular Atrophy. Current work strives to develop next generation molecules with improved properties, and to evaluate in vivo efficacy and safety of our novel compounds.
Dittrich M. Homan AE. Meriney SD. (2018) Presynaptic mechanisms controlling calcium-triggered transmitter release at the neuromuscular junction. Current Opinion in Physiology 4: 15-24.
Homan AE. Laghaei R. Dittrich M. Meriney SD. (2018) The impact of spatio-temporal calcium dynamics within presynaptic active zones on synaptic delay at the frog neuromuscular junction. Journal of Neurophysiology 119: 688-699.
Homan AE. Meriney SD. (2018) Active zone structure-function relationships at the neuromuscular junction. Synapse 72 (11): 1-11. e22057.
Meriney SD. Lacomis D. (2018) Reported direct aminopyridine effects on voltage-gated calcium channels is a high-dose pharmacological off-target effect of no clinical relevance. J. Biol. Chem. 293: 16100.
Meriney SD. Tarr TB. Ojala KS. Wu M. Li Y. Lacomis D. Garcia-Ocano A. Liang M. Valdomir G. Wipf P. (2018) Lambert-Eaton myasthenic syndrome: mouse passive-transfer model illuminates disease pathology and facilitates testing therapeutic leads. Ann. N.Y. Acad. Sci. 1412: 73-81.
Wu M. White HV. Boehm B. Meriney CJ. Kerrigan K. Frasso M. Liang M. Gotway EM. Wilcox M. Johnson JW. Wipf P. Meriney SD. (2018) New Cav2 calcium channel gating modifiers with agonist activity and therapeutic potential to treat neuromuscular disease. Neuropharmacology 131: 176-189.
Laghaei R. Ma J. Tarr TB. Homan AE. Kelly L. Tilvawala MS. Vuocolo BS. Rajasekaran HP. Meriney SD. Dittrich D. (2018) Transmitter release site organization can predict synaptic function at the neuromuscular junction. Journal of Neurophysiology 119: 1340-1355.
Ma J. Kelly L. Ingram J. Price TJ. Meriney SD. Dittrich M. (2015) New insights into short-term synaptic facilitation at the frog neuromuscular junction. Journal of Neurophysiology 113: 71-87.
Luo F. Dittrich M. Cho S. Stiles JR. Meriney SD. (2015) Transmitter release is evoked with low probability predominately by calcium flux through single channel openings at the frog neuromuscular junction. Journal of Neurophysiology 113: 2480-2489.
Tarr TB. Wipf P. Meriney SD. (2015) Synaptic pathophysiology and treatment of Lambert-Eaton myasthenic syndrome. Molecular Neurobiology 52:456-463.
Tarr TB. Lacomis D. Reddel SW. Liang M. Valdomir G. Frasso M. Wipf P. Meriney SD. (2014) Complete reversal of neuromuscular disease-induced synapse impairment by a combination of 3,4-DAP and a novel calcium channel agonist. Journal of Physiology 592: 3687-3696.
Dittrich M. Pattillo JM. King JD. Cho S. Stiles JR. Meriney SD. (2013) An excess calcium binding site model predicts neurotransmitter release at the NMJ. Biophysical Journal 104: 2751-2763.
Meriney SD. Dittrich M. (2013) Organization and function of transmitter release sites at the neuromuscular junction. Journal of Physiology 591: 3159-3165.