Enhancement of neurotransmitter release induced by brain-derived neurotrophic factor in cultured hippocampal neurons

Brain-derived neurotrophic factor (BDNF), like other neurotrophins, has lon g-term effects on neuronal survival and differentiation; furthermore, recen t work has shown that BDNF also can induce rapid changes in synaptic effica cy. We have investigated the mechanism(s) of these synaptic effects on cult ured embryonic hippocampal neurons. In the presence of the GABA(A) receptor antagonist, picrotoxin, the application of BDNF (100 ng/ml) for 1-5 min in creased the amplitude of evoked synaptic currents by 48 +/- 9% in 10 of 15 pairs of neurons and increased the frequency of EPSC bursts to 205 +/- 20% of the control levels. There was no detectable effect of BDNF on various me asures of electrical excitability, including the resting membrane potential , input resistance, action potential threshold, and action potential amplit ude. In addition, BDNF did not change the postsynaptic currents induced by the exogenous application of glutamate. BDNF did increase the frequency of miniature EPSCs (mEPSCs) (268.0 +/- 46.8% of control frequency), however, w ithout affecting the mEPSC amplitude. The effect of BDNF on mEPSC frequency was blocked by the tyrosine kinase inhibitor K252a and also by the removal of extracellular calcium ([Ca2+](o)). Fura-2 recordings showed that BDNF e licited an increase in intracellular calcium concentration ([Ca2+](c)). Thi s effect was dependent on [Ca2+](o); it was blocked by K252a and by thapsig argin, but not by caffeine. The results demonstrate that BDNF enhances glut amatergic synaptic transmission at a presynaptic locus and that this effect is accompanied by a rise in [Ca2+](c) that requires the release of Ca2+ fr om IP3-gated stores.