Endogenous TrkB ligands suppress functional mechanosensory plasticity in the deafferented spinal cord.
Dorsal root injury (DRI) disrupts the flow of sensory information to the spinal cord. Although primary afferents do not regenerate to their original targets, spontaneous recovery can, by unknown mechanisms, occur after DRI. Here, we show that brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), but not nerve growth factor or neurotrophin-4, are upregulated in the spinal gray matter after DRI. Because endogenous BDNF and NT-3 have well established roles in synaptic and axonal plasticity, we hypothesized that they contributed to spontaneous recovery after DRI. We first developed a model of DRI-induced mechanosensory dysfunction: rat C7/8 DRI produced a deficit in low-threshold cutaneous mechanosensation that spontaneously improved within 10 d but did not recover completely. To determine the effects of endogenous BDNF and NT-3, we administered TrkB-Fc or TrkC-Fc fusion proteins throughout the recovery period. To our surprise, TrkB-Fc stimulated complete recovery of mechanosensation by 6 d after DRI. It also stimulated mechanosensory axon sprouting but prevented deafferentation-induced serotonergic sprouting. TrkC-Fc had no effect on low-threshold mechanosensory behavior or axonal plasticity. There was no mechanosensory improvement with single-bolus TrkB-Fc infusions at 10 d after DRI (despite significantly reducing rhizotomy-induced cold pain), indicating that neuromodulatory effects of BDNF did not underlie mechanosensory recovery. Continuous infusion of the pan-neurotrophin antagonist K252a also stimulated behavioral and anatomical plasticity, indicating that these effects of TrkB-Fc treatment occurred independent of signaling by other neurotrophins. These results illustrate a novel, plasticity-suppressing effect of endogenous TrkB ligands on mechanosensation and mechanosensory primary afferent axons after spinal deafferentation.
Ramer
Leanne M
LM
International Collaboration on Repair Discoveries, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4.
McPhail
Lowell T
LT
Borisoff
Jaimie F
JF
Soril
Lesley J J
LJ
Kaan
Timothy K Y
TK
Lee
Jae H T
JH
Saunders
James W T
JW
Hwi
Lucy P R
LP
Ramer
Matt S
MS
D000818:Animals; D008024:Ligands; D008297:Male; D040542:Mechanotransduction, Cellular / Q000187:drug effects / Q000502:physiology*; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000819:agonists / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000503:physiopathology*
D008024:Ligands; D009414:Nerve Growth Factors; D020813:Receptor, trkB