for Project 3: During the previous grant period we made the unexpected finding that spontaneous release of vesicles (miniature endplate currents, MEPCs) plays an important role in regulating the number of releasable vesicles (n) at the mouse neuromuscular junction (NMJ) in vivo. During preliminary studies we found that reducing the binding of acetylcholine to acetylcholine receptors (AChRs) during MEPCs in an ex vivo NMJ preparation triggers an increase in n within minutes. Our preliminary data suggests this is due to alteration of a retrograde signal initiated by opening of AChRs on muscle. Taken together our findings suggest there is a continuous retrograde signal from muscle that operates on a minute by minute time scale to adjust presynaptic function of the motoneuron. Our use of an ex vivo preparation allows for detailed study of this ongoing signaling that is not possible in vivo. In this proposal we will use both in vivo and ex vivo studies to dissect the molecular signaling underlying this pathway. A better understanding of this pathway will have implications for understanding synaptic plasticity and the response of motoneurons to injury including changes in excitability and loss of synaptic inputs. We hypothesize that disruption of the trophic signaling pathway we are studying at the NMJ is a trigger that induces potentially maladaptive spinal cord plasticity following peripheral nerve injury. Our findings could have implications for the motoneuron disease spinal muscular atrophy as well as the neuromuscular disease myasthenia gravis.
Our work has implications for spinal cord function following peripheral nerve injury, the motoneuron disease spinal muscular atrophy as well as the neuromuscular disease myasthenia gravis. Our work also has basic science implications as it informs us about a signaling pathway that may play a role in synaptic plasticity at a number of synapses in the mammalian nervous system.
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|Wang, Xueyong; Pinter, Martin J; Rich, Mark M (2016) Reversible Recruitment of a Homeostatic Reserve Pool of Synaptic Vesicles Underlies Rapid Homeostatic Plasticity of Quantal Content. J Neurosci 36:828-36|
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|Koesters, Andrew; Engisch, Kathrin L; Rich, Mark M (2014) Decreased cardiac excitability secondary to reduction of sodium current may be a significant contributor to reduced contractility in a rat model of sepsis. Crit Care 18:R54|
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