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

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Glia. 2008 Jan 18;56(4):471-479

Remodeling of motor nerve terminals in demyelinating axons of

periaxin-null mice.

Court FA, Brophy PJ, Ribchester RR.

Centre for Neuroscience Research, University of Edinburgh,

Summerhall and Square, Edinburgh EH8 9JZ, United Kingdom.

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.