BDNF but not NT-4 is required for normal flexion reflex plasticity and function.
Neurotrophins can directly modulate the function of diverse types of central nervous system synapses. Brain-derived neurotrophic factor (BDNF) might be released by nociceptors onto spinal neurons and mediate central sensitization associated with chronic pain. We have studied the role of BDNF and neurotrophin-4 (NT-4), both ligands of the trkB tyrosine kinase receptor, in synaptic transmission and reflex plasticity in the mouse spinal cord. We used an in vitro spinal cord preparation to measure monosynaptic and polysynaptic reflexes evoked by primary afferents in BDNF- and NT-4-deficient mice. In situ hybridization studies show that both these neurotrophins are synthesized by sensory neurons, and NT-4, but not BDNF, also is expressed by spinal neurons. BDNF null mutants display selective deficits in the ventral root potential (VRP) evoked by stimulating nociceptive primary afferents whereas the non-nociceptive portion of the VRP remained unaltered. In addition, activity-dependent plasticity of the VRP evoked by repetitive (1 Hz) stimulation of nociceptive primary afferents (termed wind-up) was substantially reduced in BDNF-deficient mice. This plasticity also was reduced in a reversible manner by the protein kinase inhibitor K252a. Although the trkB ligand NT-4 is normally present, reflex properties in NT-4 null mutant mice were normal. Pharmacological studies also indicated that spinal N-methyl-d-aspartate receptor function was unaltered in BDNF-deficient mice. Using immunocytochemistry for markers of nociceptive neurons we found no evidence that their number or connectivity was substantially altered in BDNF-deficient mice. Our data therefore are consistent with a direct role for presynaptic BDNF release from sensory neurons in the modulation of pain-related neurotransmission.
Heppenstall
P A
PA
Growth Factors and Regeneration Group, Department of Neuroscience, Max-Delbrück Center for Molecular Medicine, D-13092 Berlin, Germany.
Lewin
G R
GR
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000502:physiology*; D009619:Nociceptors / Q000502:physiology; D012018:Reflex / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; C073922:neurotrophin 4