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.

Public Health Relevance

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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National Institute of Neurological Disorders and Stroke (NINDS)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Wright State University
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Wang, Xueyong; McIntosh, J Michael; Rich, Mark M (2018) Muscle Nicotinic Acetylcholine Receptors May Mediate Trans-Synaptic Signaling at the Mouse Neuromuscular Junction. J Neurosci 38:1725-1736
Wang, Xueyong; Rich, Mark M (2018) Homeostatic synaptic plasticity at the neuromuscular junction in myasthenia gravis. Ann N Y Acad Sci 1412:170-177
Schultz, Adam J; Rotterman, Travis M; Dwarakanath, Anirudh et al. (2017) VGLUT1 synapses and P-boutons on regenerating motoneurons after nerve crush. J Comp Neurol 525:2876-2889
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
Vincent, Jacob A; Wieczerzak, Krystyna B; Gabriel, Hanna M et al. (2016) A novel path to chronic proprioceptive disability with oxaliplatin: Distortion of sensory encoding. Neurobiol Dis 95:54-65
Romer, Shannon H; Deardorff, Adam S; Fyffe, Robert E W (2016) Activity-dependent redistribution of Kv2.1 ion channels on rat spinal motoneurons. Physiol Rep 4:
Smilde, Hiltsje A; Vincent, Jake A; Baan, Guus C et al. (2016) Changes in muscle spindle firing in response to length changes of neighboring muscles. J Neurophysiol 115:3146-55
McGovern, Vicki L; Massoni-Laporte, Aurélie; Wang, Xueyong et al. (2015) Plastin 3 Expression Does Not Modify Spinal Muscular Atrophy Severity in the ?7 SMA Mouse. PLoS One 10:e0132364
Vincent, Jacob A; Nardelli, Paul; Gabriel, Hanna M et al. (2015) Complex impairment of IA muscle proprioceptors following traumatic or neurotoxic injury. J Anat 227:221-30
Romer, Shannon H; Dominguez, Kathleen M; Gelpi, Marc W et al. (2014) Redistribution of Kv2.1 ion channels on spinal motoneurons following peripheral nerve injury. Brain Res 1547:1-15

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