BDNF/TrkB signaling regulates HNK-1 carbohydrate expression in regenerating motor nerves and promotes functional recovery after peripheral nerve repair

TY - JOUR

T1 - BDNF/TrkB signaling regulates HNK-1 carbohydrate expression in regenerating motor nerves and promotes functional recovery after peripheral nerve repair

AU - Eberhardt, Kirsten A

AU - Irintchev, Andrey

AU - Al-Majed, Abdulhakeem A

AU - Simova, Olga

AU - Brushart, Thomas M

AU - Gordon, Tessa

AU - Schachner, Melitta

PY - 2006/4

Y1 - 2006/4

N2 - Functional recovery after peripheral nerve injury is often poor despite high regenerative capacity of peripheral neurons. In search for novel treatments, brief electrical stimulation of the acutely lesioned nerve has recently been identified as a clinically feasible approach increasing precision of axonal regrowth. The effects of this stimulation appear to be mediated by BDNF and its receptor, TrkB, but the down-stream effectors are unknown. A potential candidate is the HNK-1 carbohydrate known to be selectively reexpressed in motor but not sensory nerve branches of the mouse femoral nerve and to enhance growth of motor but not sensory axons in vitro. Here, we show that short-term low-frequency electrical stimulation (1 h, 20 Hz) of the lesioned and surgically repaired femoral nerve in wild-type mice causes a motor nerve-specific enhancement of HNK-1 expression correlating with previously reported acceleration of muscle reinnervation. Such enhanced HNK-1 expression was not observed after electrical stimulation in heterozygous BDNF or TrkB-deficient mice. Accordingly, the degree of proper reinnervation of the quadriceps muscle, as indicated by retrograde labeling of motoneurons, was reduced in TrkB+/- mice compared to wild-type littermates. Also, recovery of quadriceps muscle function, evaluated by a novel single-frame motion analysis approach, and axonal regrowth into the distal nerve stump, assessed morphologically, were considerably delayed in TrkB+/- mice. These findings indicate that BDNF/TrkB signaling is important for functional recovery after nerve repair and suggest that up-regulation of the HNK-1 glycan is linked to this phenomenon.

AB - Functional recovery after peripheral nerve injury is often poor despite high regenerative capacity of peripheral neurons. In search for novel treatments, brief electrical stimulation of the acutely lesioned nerve has recently been identified as a clinically feasible approach increasing precision of axonal regrowth. The effects of this stimulation appear to be mediated by BDNF and its receptor, TrkB, but the down-stream effectors are unknown. A potential candidate is the HNK-1 carbohydrate known to be selectively reexpressed in motor but not sensory nerve branches of the mouse femoral nerve and to enhance growth of motor but not sensory axons in vitro. Here, we show that short-term low-frequency electrical stimulation (1 h, 20 Hz) of the lesioned and surgically repaired femoral nerve in wild-type mice causes a motor nerve-specific enhancement of HNK-1 expression correlating with previously reported acceleration of muscle reinnervation. Such enhanced HNK-1 expression was not observed after electrical stimulation in heterozygous BDNF or TrkB-deficient mice. Accordingly, the degree of proper reinnervation of the quadriceps muscle, as indicated by retrograde labeling of motoneurons, was reduced in TrkB+/- mice compared to wild-type littermates. Also, recovery of quadriceps muscle function, evaluated by a novel single-frame motion analysis approach, and axonal regrowth into the distal nerve stump, assessed morphologically, were considerably delayed in TrkB+/- mice. These findings indicate that BDNF/TrkB signaling is important for functional recovery after nerve repair and suggest that up-regulation of the HNK-1 glycan is linked to this phenomenon.

KW - Animals

KW - Axotomy/methods

KW - Brain-Derived Neurotrophic Factor/deficiency

KW - CD57 Antigens/metabolism

KW - Disease Models, Animal

KW - Electric Stimulation/methods

KW - Femoral Nerve/cytology

KW - Gene Expression Regulation/radiation effects

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Motor Neurons/pathology

KW - Nerve Regeneration/physiology

KW - Peripheral Nerves/pathology

KW - Peripheral Nervous System Diseases/physiopathology

KW - Receptor, trkB/deficiency

KW - Recovery of Function/physiology

KW - Signal Transduction/physiology

KW - Time Factors

U2 - 10.1016/j.expneurol.2005.12.018

DO - 10.1016/j.expneurol.2005.12.018

M3 - SCORING: Journal article

C2 - 16460731

VL - 198

SP - 500

EP - 510

JO - EXP NEUROL

JF - EXP NEUROL

SN - 0014-4886

IS - 2

ER -