Abstract
Recently, we have shown that manual stimulation of paralyzed vibrissal muscles after facial-facial anastomosis reduced the poly-innervation of neuromuscular junctions and restored vibrissal whisking. Using gene knock outs, we found a differential dependence of manual stimulation effects on growth factors. Thus, insulin-like growth factor-1 and brain-derived neurotrophic factor are required to underpin manual stimulation-mediated improvements, whereas FGF-2 is not. The lack of dependence on FGF-2 in mediating these peripheral effects prompted us to look centrally, i.e. within the facial nucleus where increased astrogliosis after facial-facial anastomosis follows "synaptic stripping". We measured the intensity of Cy3-fluorescence after immunostaining for glial fibrillary acidic protein (GFAP) as an indirect indicator of synaptic coverage of axotomized neurons in the facial nucleus of mice lacking FGF-2 (FGF-2-/- mice). There was no difference in GFAP-Cy3-fluorescence (pixel number, gray value range 17–103) between intact wildtype mice (2.12± 0.37×107) and their intact FGF-2-/- counterparts (2.12± 0.27×107) nor after facial-facial anastomosis +handling (wildtype: 4.06± 0.32×107; FGF-2-/-: 4.39±0.17×107). However, after facial-facial anastomosis, GFAP-Cy3-fluorescence remained elevated in FGF-2-/--animals (4.54±0.12×107), whereas manual stimulation reduced the intensity of GFAP-immunofluorescence in wild type mice to values that were not significantly different from intact mice (2.63± 0.39×10 ). We conclude that FGF-2 is not required to underpin the beneficial effects of manual stimulation at the neuro-muscular junction, but it is required to minimize astrogliosis in the brainstem and, by implication, restore synaptic coverage of recovering facial motoneurons.
Highlights
Restoration of function after transection of peripheral nerves is poor
We have shown that manual stimulation of paralyzed vibrissal muscles after facial-facial anastomosis reduced the poly-innervation of neuromuscular junctions and restored vibrissal whisking
With respect to functional improvements, we have recently shown that after facial nerve injury, manual stimulation (MS) of denervated whisker pads reduces the proportion of polyinnervated neuro-muscular junctions (NMJ)
Summary
Restoration of function after transection of peripheral nerves is poor. Occurrence of "post-paralytic syndromes" such as paresis, synkinesis and dysreflexia are inevitable. Axonal regrowth is robust, a large body of evidence points to poor recovery being attributable, at least in part, to extensive sprouting and inaccurate reinnervation of target muscles. Axonal sprouting occurs at a number of locations en route along the axis of the facial nucleus - facial-nerve trunk - facial nerve fascicles - facial, [2] muscles. The quality of peripheral nerve regeneration, both within the nerve and at the motor end-plate/terminal Schwann cell complex, can be improved by various non-invasive therapies. Muscles with flaccid paralysis can be stimulated electrically or by exercise, procedures which inhibit intramuscular axonal sprouting and diminish motor-end-plate polyinnervation, thereby improving reinnervation quality[3]
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