Abstract
In addition to their classical roles in neuronal growth, survival and differentiation, neurotrophins are also rapid regulators of excitability, synaptic transmission and activity-dependent synaptic plasticity. We have recently shown that mature BDNF (Brain Derived Neurotrophic Factor), but not proBDNF, modulates the excitability of interneurons in dentate gyrus within minutes. Here, we used brain slice patch-clamp recordings to study the mechanisms through which BDNF modulates the firing of interneurons in rat dentate gyrus by binding to TrkB receptors. Bath application of BDNF (15 ng/ml) under current-clamp decreased the firing frequency (by 80%) and input resistance, blocking the delayed firing observed at near-threshold voltage ranges, with no changes in resting membrane potential or action potential waveform. Using TEA (tetraethylammonium), or XE991(a Kv7/KCNQ channel antagonist), the effect of BDNF was abolished, whereas application of retigabine (a Kv7/KCNQ channel opener) mimicked the effect of BDNF, suggesting that the M-current could be implicated in the modulation of the firing. In voltage-clamp experiments, BDNF increased the M-like current amplitude with no change in holding current. This effect was again blocked by XE991 and mimicked by retigabine, the latter accompanied with a change in holding current. In agreement with the electrophysiology, parvalbumin-positive interneurons co-expressed TrkB receptors and Kv7.2/KCNQ2 channels. In conclusion, BDNF depresses the excitability of interneurons by activating an M-like current and possibly blocking Kv1 channels, thereby controlling interneuron resting membrane potential and excitability.
Highlights
Brain-derived neurotrophic factor (BDNF) is an important neurotrophin involved in the regulation of neuron survival and differentiation during development [1]
Since potassium conductances generally regulate neuronal excitability [10] and Kv7/KCNQ/M channels control interspike interval in interneurons [8], we investigated whether M-channels could be modulated by BDNF
We studied the mechanism through which BDNF modulates the firing of parvalbumin-positive interneurons in rat dentate gyrus
Summary
Brain-derived neurotrophic factor (BDNF) is an important neurotrophin involved in the regulation of neuron survival and differentiation during development [1]. BDNF has rapid cellular actions, including effects on neuronal excitability, synaptic transmission, and plasticity [1,3,4] For this to occur, BDNF acts by binding to two types of plasma membrane receptors, the Trk receptor tyrosine kinase B (TrkB) or the p75 pan-neurotrophin receptor (p75NTR;[5]). We described that mature BDNF, but not proBDNF, depresses the excitability of fast-spiking parvalbumin-positive interneurons within minutes [7]. This effect was mediated by activation of TrkB, and not p75NTR, and led to a decreased firing upon interneuron depolarization with little or no change in other electrophysiological parameters. It can be hypothesized that BDNF-mediated TrkB activation may lead to a rapid modulation of ion channels in the interneuron membrane
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