NT-3 null mutant mice display a postnatal motor neuropathy

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Eur J Neurosci. 2005 Apr;21(8):2100-2110.

Neurotrophin-3 null mutant mice display a postnatal motor neuropathy.

Woolley AG, Sheard PW, Duxson MJ.

Department of Anatomy & Structural Biology, Otago School of Medical

Sciences, University of Otago, PO Box 913, Dunedin, New Zealand.

Abstract: This paper examines early postnatal development of the

neuromuscular system in mice with a null mutation in the gene for

neurotrophin-3.

We report that alpha-motoneurons at first develop substantially

normally, despite a known 15% deficit in their somal size [Woolley et

al. (1999)Neurosci. Lett., 272, 107-110.] and the absence of

proprioceptive input [Ernfors et al. (1994)Cell, 77, 503-512]. At

birth, motor axons have extended into the muscle, forming normal-

looking neuromuscular junctions with focal accumulations of

acetylcholine receptors.

Detailed ultrastructural analysis does however, reveal subtle

abnormalities at this time, particularly a decrease in the extent of

occupancy of the postsynaptic site by nerve terminals, and a small

but significant deficit in myofibre number. After the relative

normality of this early neuromuscular development, there then occurs

a catastrophic postnatal loss of motor nerve terminals, resulting in

complete denervation of hindlimb muscles by P7.

In systematic semi-serial samples through the entire muscle endplate

zones, no neuromuscular junctions can be found. Intramuscular axons

are fragmented, as shown by both electron microscopic observations

and neurofilament immunohistochemistry, and alpha-bungarotoxin

detection of acetylcholine receptors indicates dispersal of the

junctional accumulation. At earlier times (postnatal days three and

four) the terminal Schwann cells show ultrastructural abnormalities,

and preliminary observations suggest marked disturbance of

myelination.

Based on comparison with other literature, the peripheral nerve

degeneration seems unlikely to have arisen as a secondary effect of

de-afferentation. We discuss whether the neural degeneration is

secondary to the disturbance of Schwann cell function, or due

directly to a loss of neurotrophin-3 based support of the motoneuron.