Remodeling of motor nerve terminals in demyelinating axons of periaxin-null mice.

Myelin formation around axons increases nerve conduction velocity and influences both the structure and function of the myelinated axon. In the peripheral nervous system, demyelinating forms of hereditary Charcot-Marie-Tooth (CMT) diseases cause reduced nerve conduction velocity initially and ultimately axonal degeneration. Several mouse models of CMT diseases have been generated, allowing the study of the consequences of disrupting Schwann cell function on peripheral nerve fibers. Nevertheless, the effect of demyelination at the level of the neuromuscular synapse has been largely overlooked. Here we show that in mice lacking functional Periaxin (Prx) genes, a model of a recessive type of CMT disease known as CMT4F, neuromuscular junctions (NMJs) develop profound morphological changes in the preterminal region of motor axons. These changes include extensive preterminal branches that originate in demyelinated regions of the nerve fiber and axonal swellings associated with residually-myelinated regions of the fiber. Using intracellular recording from muscle fibers we detected asynchronous failure of action potential transmission at high but not low stimulation frequencies, a phenomenon consistent with branch point failure. Taken together, our morphological and electrophysiological findings suggest that preterminal branching due to segmental demyelination near the neuromuscular synapse in Periaxin KO mice may underlie some characteristics of disabilities, including coordination deficits, present in this mouse model of CMT disease. These results reveal the importance of studying how demyelinating diseases might influence NMJ function and contribute to clinical disability.