Neuropharmacology

Biography

Biography: Miguel A Morales

Abstract

Among their synaptic regulatory actions, neurotrophins (NTs) modulate long term potentiation (LTP). We have shown a differential modulation of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) on sympathetic ganglia LTP (gLTP). BDNF increases gLTP, while NGF produces a concentration-dependent opposite modulation, at 200 ng/ml depresses whereas at 500 ng/ml enhances gLTP. Our work is consistent with the view that gLTP results from an increase in ganglionic synaptic efficacy, and that NTs regulate neuronal excitability. We propose that gLTP enhancement results from the synchronization of a large number of neurons firing phasically, then we postulate that BDNF and NGF 500 increase gLTP by inducing neurons to fire phasically. On the contrary, NGF 200 induces neurons to fire tonically. Herein we studied their contribution of KCNQ/M-currents in setting neuronal activity responsible of neurotrophin-dependent gLTP modulation. We characterized the effects of KCNQ channels agonists and antagonists on gLTP evoked by 40 Hz, 5s stimulation of superior cervical ganglia in vitro. We found that flupirtine, an agonist of Kv7/KCNQ channels, mimicked the stimulatory effects of BDNF and NGF 500 ng/ml on gLTP. While the Kv7/KCNQ channel antagonist XE991 mimicked the decreasing effect of NGF 200 ng/ml, and abolished the stimulatory effect of BDNF and NGF 500 ng/ml. Our data suggest that M-currents contribute to the mechanisms activated by NTs to set the neuronal excitability that underlie gLTP. We propose that gLTP enhancement results from the synchronization of a large number of neurons firing phasically, and that BDNF and NGF 500 ng/ml by activating Kv7 channels reinforce this neuronal firing pattern and thereby increase gLTP. On the contrary, NGF 200 ng/ml by inhibiting these channels induces neurons to fire tonically producing gLTP reduction.