PATHOPHYSIOLOGICAL STUDY OF AXONAL DEGENERATION IN THE GRACILE AXONAL DYSTROPHY (GAD) MUTANT MOUSE

The gracile axonal dystrophy (gad) mouse, which shows hereditary sensory ataxia and motor paresis, has been morphologically characterized by the dying back type of axonal degeneration in the nerve terminals of dorsal root ganglion cells and motor neurons. In the present study, developmental changes in the functional properties of peripheral nerves were investigated in the gad mouse using electrophysiological and immunohistochemical methods. In the gastrocnemius muscle of the gad mouse, the incidence of fibrillation increased with age. Although the conduction velocity of the tibial nerve stayed within the normal range, the amplitude of the M wave decreased significantly with age in this mutant. Ligation study of the sciatic nerve showed that both antero- and retrograde axonal transport was functional in the gad mouse even when the disease had fully progressed. The morphometry of the sciatic nerve showed no differences between gad and control mice. Nicotinic acetylcholine receptors started to disperse over the surface of skeletal muscles in the gad mouse after 11 weeks of age when motor paresis was clinically manifested. Our results show that the function of peripheral nerve of the gad mouse decreases with age through an axonal degeneration process. The possibility raised by previous morphological studies that the dysfunction of axonal transport causes the pathogenesis of the gad mouse is unlikely.