Aperghis, Michael David; (2003) Effect of the peripheral target on motoneuron survival, emphasising the role of a locally acting splice variant of IGF-1. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

While it is clear that target tissue and the periphery in general play an important role for the survival and maintenance of motoneurons, the underlying mechanisms remain unclear. The experiments described in this thesis use a model of axotomy-induced motoneuron death to study the effect of insulin-like growth factor-1 (IGF-1) isoforms, diet and muscle damage on the survival of adult facial motoneurons. Particular attention is paid to the effects on motoneurons of the autocrine/paracrine-acting splice variant of IGF-1 (MGF), which has been isolated recently from active skeletal muscle. Using stereological methods, it was found that facial nerve avulsion of ad libitum-fed adult rats resulted in approximately 80% loss of motoneurons. However, diet restriction, which is known to alter IGF-1 levels, of rats from the age of 6 months reduced the number of facial motoneurons by about 50% at 24 months-of-age but prevented any further loss of motoneurons following facial nerve avulsion. These results challenge the common view that diet restriction is universally beneficial. MGF gene transfer prior to nerve avulsion conferred marked neuroprotection of facial motoneurons at 1-month post injury. Such neuroprotection was approximately two-fold greater than that obtained with the liver-type IGF-1 (endocrine) splice variant. MGF E-domain peptide delivered to avulsed motoneurons also protected motoneurons at 1 month. In addition to MGF gene transfer, muscle denervation was also associated with perturbations of MGF mRNAs. Direct damage to target-muscle prior to nerve avulsion rendered motoneurons more resistant to death. Specific markers for motoneuron survival, death, regeneration and neuroglial activation were used throughout the study to characterise the response of motoneurons to nerve avulsion. The results are discussed in the context of current theories of motoneuron target-dependence and the possible neurotrophic effects of MGF.

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