Lack of motor recovery after prolonged denervation of the neuromuscular junction is not due to regenerative failure.
Motor axons in peripheral nerves have the capacity to regenerate after injury. However, full functional motor recovery rarely occurs clinically, and this depends on the nature and location of the injury. Recent preclinical findings suggest that there may be a time after nerve injury where, while regrowth to the muscle successfully occurs, there is nevertheless a failure to re-establish motor function, suggesting a possible critical period for synapse reformation. We have now examined the temporal and anatomical determinants for the re-establishment of motor function after prolonged neuromuscular junction (NMJ) denervation in rats and mice. Using both sciatic transection-resuture and multiple nerve crush models in rats and mice to produce prolonged delays in reinnervation, we show that regenerating fibres reach motor endplates and anatomically fully reform the NMJ even after extended periods of denervation. However, in spite of this remarkably successful anatomical regeneration, after 1 month of denervation there is a consistent failure to re-establish functional recovery, as assessed by behavioural and electrophysiological assays. We conclude that this represents a failure in re-establishment of synaptic function, and the possible mechanisms responsible are discussed, as are their clinical implications.
Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA.|Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA.
Miyuki
M
Sakuma
Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA.|Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA.
Grzegorz
G
Gorski
Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA.|Department of Pathology and Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
Shu-Hsien
SH
Sheu
Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA.|Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA.
Stella
S
Lee
Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA.|Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA.
Lee B
LB
Barrett
Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA.|Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA.
Bhagat
B
Singh
Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA.|Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA.
Takao
T
Omura
Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA.|Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA.
Alban
A
Latremoliere
Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA.|Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA.
Clifford J
CJ
Woolf
D000818:Animals; D003714:Denervation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000502:physiology*; D009416:Nerve Regeneration; D009469:Neuromuscular Junction / Q000502:physiology*; D059348:Peripheral Nerve Injuries / Q000534:rehabilitation* / Q000601:surgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D012584:Sciatic Nerve / Q000502:physiology* / Q000601:surgery
critical period; motor functional recovery; neuromuscular junction; peripheral nerve injury; regeneration