Patients with Charcot-Marie-Tooth Type2D (CMT2D) develop an axonopathy that becomes relatively stable and progresses slowly. Patients also complain of weakness and fatigue for which underlying mechanisms are unknown and difficult to treat. Much work has focused on the mechanisms of axon loss but, to our knowledge, there has been little study of remaining intact synaptic connections. Whether existing synapses function normally or not and whether abnormal function proceeds axon loss is unknown. Preliminary data from recently described mouse models of CMT2D revealed that neuroumuscular transmission is abnormal. In this project, we will confirm the nature of the synaptic deficits and the underlying cause. In addition, we will determine whether enhancing neuromuscular transmission, using currently available drugs (3,4-DAP, physostigmine) for treatment of myasthenias, can improve overall function of the mice. This drug is known to enhance synaptic function and to improve motor abilities in patients with myasthenias, but to our knowledge, it has never been used in treatment of CMTs. We will employ a combination of electrophysiology and microscopy to measure synaptic function directly and evaluate the structural integrity of the synapses. This will provide a detailed understanding of the basis for the synaptic deficits observed in preliminary experiments. Finally, tests of motor behavior will be used to evaluate whole animal motor performance in a comparison of treated versus untreated CMT2D mice. This work is the initial step in assessing the possibility of using 3,4-DAP and/or physostigmine to treat CMT2D patients.

Public Health Relevance

Charcot-Marie-Tooth Type2D (CMT2D) is a chronic slowly progressive disease that creates variable degrees of disability. Patients often complain of weakness and fatigue of unknown origin. One possible origin of this fatigue and weakness, that to our knowledge has not been investigated, is impaired synaptic transmission at neuromuscular synapses. Identification and characterization of synaptic dysfunction would open the door for possible new treatments that targeted the impaired synaptic transmission. We propose to characterize synaptic function in two murine alleles that are accurate models of CMT2D, as a first step toward possible identification of new treatment options.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Research Grants (R03)
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Cell Death and Injury in Neurodegeneration Study Section (CDIN)
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Gwinn, Katrina
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Jackson Laboratory
Bar Harbor
United States
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Spaulding, Emily L; Sleigh, James N; Morelli, Kathryn H et al. (2016) Synaptic Deficits at Neuromuscular Junctions in Two Mouse Models of Charcot-Marie-Tooth Type 2d. J Neurosci 36:3254-67
Seburn, Kevin L; Morelli, Kathryn H; Jordanova, Albena et al. (2014) Lack of neuropathy-related phenotypes in hint1 knockout mice. J Neuropathol Exp Neurol 73:693-701