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"PATHOPHYSIOLOGY OF NEUROMUSCULAR JUNCTIONS DURING MYASTHENIA GRAVIS RESULTING FROM AUTOIMMUNITY TO MUSCLE SPECIFIC TYROSINE KINASE"

by
Vishwendra Patel
Pharmacology & Physiology Program
B.S., 2003, All India Institute of Medical Sciences, New Delhi, India
M.S., 2006, All India Institute of Medical Sciences, New Delhi, India

Thesis Advisor: Joseph J. McArdle, Ph.D.
Professor
Department of Pharmacology & Physiology

Thursday, November 7, 2013
12:00 P.M., MSB H-609


Abstract

Autoantibodies to muscle specific tyrosine kinase (MuSK) and the acetylcholine receptor (AChR) produce distinct forms of myasthenia gravis (MG). Unlike AChR-MG, MuSK-MG patients do not undergo significant loss of AChRs and are refractory to anticholinesterase drug therapy. Studies of experimental models suggest that loss of endplate AChRs due to MuSK autoantibodies or decline of motor nerve function is the primary cause of MuSK-MG. To enhance understanding of MuSK-MG pathophysiology I studied C57B6 female mice injected with 40 µg of rat MuSK ectodomain once a month for 3 months. While all immunized mice produced MuSK antibodies, symptoms of MG varied. Since in vivo plethysmography indicated that respiratory muscle function was severely altered, I measured force production for phrenic nerve – diaphragm muscle preparations. Twitch and tetanic responses to phrenic nerve stimulation were significantly less than control for 40% of MuSK-injected mice. Affected MuSK-MG mice provided nerve-muscle preparations for electrophysiologic, morphologic, biochemical, and pharmacologic study. Endplate current (EPC) measurements indicated that neuromuscular transmission declined progressively in three stages. In stage 1, EPC quantal content was significantly less than control although failures of EPC initiation were never observed. During stage 2, reduced quantal content accompanied an intermittent failure of EPC initiation that was associated with failure of action potential propagation into the motor nerve terminal. During stage 3, stimulus-evoked EPCs were absent at “silent” neuromuscular junctions that produced spontaneous miniature EPCs. Failure of impulse propagation into and evoked transmitter release from the motor nerve terminal during stages 2 and 3 is attributed to altered motor nerve morphology. The decline of stimulus-evoked transmitter release accompanied reductions of the probability of vesicle release, the number of release sites, the functional store of synaptic vesicles, as well as skewing of the miniature EPC amplitude distribution to smaller values. A prolonged decay of EPCs for MuSK-MG mice was due to a decline of acetylcholine esterase activity and not to expression of the embryonic AChR. Although there was also a 20% decline of AChR enriched endplate area this cannot account for the severe depression of neuromuscular transmission. These data support the hypothesis that motor nerve abnormalities are key determinants of reduced neuromuscular transmission during MuSK-MG. Therefore, I studied novel drug targets for the therapy of MuSK-MG.


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