Nerve growth factor regulates the firing patterns and synaptic composition of motoneurons.
Target-derived neurotrophins exert powerful synaptotrophic actions in the adult brain and are involved in the regulation of different forms of synaptic plasticity. Target disconnection produces a profound synaptic stripping due to the lack of trophic support. Consequently, target reinnervation leads to synaptic remodeling and restoration of cellular functions. Extraocular motoneurons are unique in that they normally express the TrkA neurotrophin receptor in the adult, a feature not seen in other cranial or spinal motoneurons, except after lesions such as axotomy or in neurodegenerative diseases like amyotrophic lateral sclerosis. We investigated the effects of nerve growth factor (NGF) by retrogradely delivering this neurotrophin to abducens motoneurons of adult cats. Axotomy reduced the density of somatic boutons and the overall tonic and phasic firing modulation. Treatment with NGF restored synaptic inputs and firing modulation in axotomized motoneurons. When K252a, a selective inhibitor of tyrosine kinase activity, was applied to specifically test TrkA effects, the NGF-mediated restoration of synapses and firing-related parameters was abolished. Discharge variability and recruitment threshold were, however, increased by NGF compared with control or axotomized motoneurons. Interestingly, these parameters returned to normal following application of REX, an antibody raised against neurotrophin receptor p75 (p75(NTR)). In conclusion, NGF, acting retrogradely through TrkA receptors, supports afferent boutons and regulates the burst and tonic signals correlated with eye movements. On the other hand, p75(NTR) activation regulates recruitment threshold, which impacts on firing regularity. To our knowledge, this is the first report showing powerful synaptotrophic effects of NGF on motoneurons in vivo.
Davis-López de Carrizosa
María A
MA
Departamento de Fisiología y Zoología, Facultad de Biología, Universidad de Sevilla, 41012 Sevilla, Spain.
Morado-Díaz
Camilo J
CJ
Morcuende
Sara
S
de la Cruz
Rosa R
RR
Pastor
Angel M
AM
D000010:Abducens Nerve / Q000502:physiology; D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D019771:Axotomy / Q000379:methods; D001933:Brain Stem / Q000166:cytology; D002227:Carbazoles / Q000494:pharmacology; D002415:Cats; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005133:Eye Movements / Q000502:physiology; D005260:Female; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects; D016370:Gene Products, rex / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D026121:Indole Alkaloids / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology*; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism; D011999:Recruitment, Neurophysiological / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D016708:Synaptophysin / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
D002227:Carbazoles; D004791:Enzyme Inhibitors; D016370:Gene Products, rex; D005904:Glial Fibrillary Acidic Protein; D026121:Indole Alkaloids; D020800:Receptor, Nerve Growth Factor; D016708:Synaptophysin; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C493406:vesicular GABA transporter; D020932:Nerve Growth Factor; C049985:staurosporine aglycone; D002795:Choline O-Acetyltransferase; D020917:Receptor, trkA