Compartmental neurodegeneration and synaptic plasticity in the Wld(s) mutant mouse

Abstract

This review focuses on recent developments in our understanding of neurodegeneration at the mammalian neuromuscular junction. We provide evidence to support a hypothesis of compartmental neurodegeneration, whereby synaptic degeneration occurs by a separate, distinct mechanism from cell body and axonal degeneration. Studies of the spontaneous mutant Wld(s) mouse, in which Wallerian degeneration is characteristically slow, provide key evidence in support of this hypothesis. Some features of synaptic degeneration in the absence of Wallerian degeneration resemble synapse elimination in neonatal muscle. This and other forms of synaptic plasticity may be accessible to further investigations, exploiting advantages afforded by the Wld(s) mutant, or transgenic mice that express the Wld(s) gene.

Figure 1. Schematic representation of Wallerian degeneration

A, the cellular organisation of a motoneurone, skeletal muscle fibre and Schwann cells. B, following an axonal lesion, the distal stump of the axon and its motor nerve terminal degenerate. The resident Schwann cells dedifferentiate and proliferate. The axonal, nerve terminal and myelin debris are removed by phagocytosing Schwann cells as well as invading macrophages. The cell body undergoes chromatolysis and the nucleus translocates. C, after the removal of all debris and the formation of bands of Büngner by Schwann cells, the proximal nerve stump regenerates back to the denervated muscle fibre. (Adapted from Nicholls et al. (1992) with permission.)

Figure 2. Genetics of the Wld^s mouse

Location of exons within the 85 kb triplication repeat unit in the Wld^s mutant mouse, showing the formation of the Ufd2-Nmnat chimeric gene and the triplication of the complete Rbp7 gene. (Based on Conforti et al. (2000).)

Figure 3. Piecemeal withdrawal of motor nerve terminals at axotomised Wld^s NMJs

Electrophysiological, immunocytochemical and ultrastructural correlates of control, withdrawing and vacant NMJs. Control preparations (A) have strong endplate potentials, exact matching of pre- and postsynaptic components and a healthy distribution of mitochondria and clear 50 nm synaptic vesicles within terminal boutons. Withdrawing terminals (B) show a weakening of synaptic transmission as well as piecemeal retraction of boutons. Ultrastructurally, withdrawing boutons appear normal (with intact mitochondria and normal vesicle numbers) except for the accumulation of neurofilaments within the terminal. Vacant and nearly vacant endplates (C) show no electrophysiological activity and nerve terminals are sometimes replaced at the synaptic site by Schwann cells. The axon shown stained with neurofilament and SV2 antibodies ends in two ‘retraction bulbs’ resembling structures seen during neonatal synapse elimination. (Authors’ unpublished data.)

Figure 4. Compartmental organisation of degeneration mechanisms in the neurone based on the present review

Genes regulating cell body degeneration by apoptosis (blue) and axon degeneration (magenta) are given in parentheses. The genes controlling synaptic degeneration (Synaptosis; yellow) have not yet been defined.