Reinnervation

Figure 15. Grouping of muscle fibers of uniform histochemical type indicating reinnervation in a patient with SMA.

The clinical and histopathological features of individual neurogenic muscle disorders are determined to a large extent by the balance of the opposing processes of denervation and reinnervation, at least as far as the muscle dysfunction is concerned. The involvement of upper motor neurons in some of these disorders is outside the scope of this chapter and will only be referred to in passing. 

Kugelberg-Welander disease (type III SMA) is characterized by juvenile onset and prolonged survival. In early stages of the disease the process of reinnervation... 

Molliver, M.E. Mamounas, L.A. and Carr, P. Reinnervation of cerebral cortex by 5-HT axons after denervation by psychotropic amphetamine derivatives. Abstr Soc Neurosci 15 5687, in press. 

One of the striking aspects of this toxicity of compounds is selective destruction terminals and the cell bodies that are left intact. Dr. De Souza has recently reported some biochemical evidence for recovery of serotonin. We have now found anatomic evidence for reinnervation of depleted areas by serotonin neurons. But it is going to be a while before we figure out whether their reinnervation is appropriate or perhaps aberrant. Do they end up with complete recovery, do they end up with a better system than they started with or one that malfunctions I think that is an important area for future study. 

A reduction of HED uptake in patients with moderate heart failure is a predictor of poor outcome, a finding consistent with SPECT MIBG studies [137]. HED PET imaging demonstrates reinnervation of the transplanted heart [138] paralleling recovery of primarily fatty acids metabolism after an initial metabolic shift from fatty acids to glucose utilization associated with myocardial denervation [139]. 

EstorchM, Camprecios M, Flotats A, Mari C, Berna L, Catafau AM et al. Sympathetic reinnervation of cardiac allografts evaluated by 123I-MIBG imaging. J Nucl Med 1999 40 911-916... 

E.L. Fallen, G. Coates, C. Nahmias, R. Chlrakal, R. Beanlands, L. Wahl, G. Woodcock, M. Thomson, M. Kamath, Recovery rates of regional sympathetic reinnervation and myocardial blood flow after acute myocardial Infarction, Am. Heart J. 137 (1999) 863-869. 

Wilson RF et al Regional differences in sympathetic reinnervation after human orthotopic cardiac transplantation. Circulation 1993 88 165. [PMID 8319329]... 

Fray, Paul J., Stephen B. Dunnett, Susan D. Iversen, Anders Bjorklund and Ulf Stenevi. 1983. "Nigral Transplants Reinnervating the Dopamine-Depleted Neostriatum Can Sustain Intracranial Self-Stimulation." Science 219 416-19. 

Degenerating axons in the peripheral nerves can also be examined as described below, and electrophysiological estimates of motor unit number could be informative. Motor units are defined as a single motor neuron (axon) and the muscle fibers its terminals innervate. In motor neuron diseases, the number of motor units is anticipated to decrease as motor neurons die, but the size of motor units may increase with compensatory sprouting and reinnervation (e.g., (1)). Interpretation can be further confounded by factors such as a change in muscle fiber number or innervation of muscle fibers by multiple motor axons. Therefore, the best interpretation results from corroborating evidence from the spinal cord, nerve, synapse, and the muscle. 

Additional analyses that can be informative include staining with anti-SlOO to visualize Schwann cells (the terminal Schwann cells play an important role in guiding terminal sprouting and reinnervation (5, 6)) and histochemical stains to visualize acetylcholine esterase (7). 

Most animals with small lesions and many with intermediate lesions turned left or have only a modest tendency to turn toward the side of the lesion (right side). Only animals with large lesions persist in turning toward the lesioned side. Thus amphetamine induced turning provides a functional measure of the degree to which regenerated dopamine terminals can release dopamine. Amphetamine induced rotation is therefore a better measure of the degree of functional reinnervation rather than the size of a lesion. 

Fagan AM, Gage FH (1994) Mechanisms of sprouting in the adult central nervous system cellular responses in areas of terminal degeneration and reinnervation in the rat hippocampus. Neuroscience 58 105-125. 

Raisman G, Field PM (1973) A quantitative investigation of the development of collateral reinnervation after partial deafferentation of the septal nuclei. Brain Res 50 241-264. 

Bjorklund A, Dunnett SB, Stenevi U, Lewis ME, Iversen SD (1980) Reinnervation of the denervated striatum by substantia nigra transplants functional consequences as revealed by pharmacological and sensorimotor testing. Brain Res 799 307-333. 

Rosenblad C, Kirik D, Bjorklund A (2000) Sequential administration of GDNF into the substantia nigra and striatum promotes dopamine neuron survival and axonal sprouting but not striatal reinnervation or functional recovery in the partial 6-OHDA lesion model. Exp Neurol 767 503-516. 

In a recent study, scientists directed mouse embryonic stem cells to differentiate into DA neurons by introducing the gene Nurr 1. When transplanted into the brains of a rat model of Parkinson s disease, these stem cell-derived DA neurons reinnervated the brains of the mouse Parkinson s disease model, released dopamine, and improved motor function. 

---