Enhancement of Neurotransmitter Release Induced by Brain-Derived Neurotrophic Factor in Cultured Hippocampal Neurons

Abstract

Brain-derived neurotrophic factor (BDNF), like other neurotrophins, has long-term effects on neuronal survival and differentiation; furthermore, recent work has shown that BDNF also can induce rapid changes in synaptic efficacy. We have investigated the mechanism(s) of these synaptic effects on cultured embryonic hippocampal neurons. In the presence of the GABAA receptor antagonist, picrotoxin, the application of BDNF (100 ng/ml) for 1-5 min increased 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 measures of electrical excitability, including the resting membrane potential, input resistance, action potential threshold, and action potential amplitude. 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, without 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 elicited an increase in intracellular calcium concentration ([Ca2+]c). This effect was dependent on [Ca2+]o; it was blocked by K252a and by thapsigargin, but not by caffeine. The results demonstrate that BDNF enhances glutamatergic synaptic transmission at a presynaptic locus and that this effect is accompanied by a rise in [Ca2+]c that requires the release of Ca2+ from IP3-gated stores.

BDNF and NT-3 Increase Velocity of Activity Front Propagation in Unidimensional Hippocampal Cultures

“…Thus the measured effects that we report here were long-term and not acute, as previously studied in BDNF (Brunig et al 2001;Frerking et al 1998;Kang and Schuman 1995;Kim et al 1994;Levine et al 1995;Li et al 1998;Tanaka et al 1997) or NT-3 (Kang and Schuman 1995;Kim et al 1994).…”

Neurotrophin signaling among neurons and glia during formation of tripartite synapses

“…Reducing BDNF signaling by scavenging BDNF with TrkB-IgG fusion proteins decreases mEPSC frequency in hippocampal neurons (Cabelli et al, 1997). Consistent with these findings, BDNF enhances glutamatergic transmission at mature hippocampal synapses, in part by increases in presynaptic glutamate release (Kang and Schuman, 1996;Carmignoto et al, 1997;Li et al, 1998). At hippocampal and cortical synapses in vivo and in vitro, BDNF facilitates long-term potentiation, attenuates long-term depression and promotes homeostatic and competitive interactions that refine neural circuitry (Korte et al, 1995;Akaneya et al, 1996;Cabelli et al, 1996;Huang et al, 1999;Turrigiano and Nelson, 2000;Turrigiano and Nelson, 2004).…”

BDNF-induced local protein synthesis and synaptic plasticity

“…At the presynaptic level the activation of TrkB receptors was shown to upregulate depolarization-evoked glutamate release from isolated hippocampal and cerebrocortical synaptosomes (Jovanovic et al, 2000;Pascual et al, 2001;Pereira et al, 2006;Simsek-Duran and Lonart, 2008). Studies performed in cultured hippocampal neurons showed that BDNF increases the frequency of miniature excitatory postsynaptic currents, further supporting a presynaptic effect of the neurotrophin (Lessmann and Heumann, 1998;Li et al, 1998;Schinder et al, 2000;Tyler and Pozzo-Miller, 2001). The rapidly recycling pool of synaptic vesicles is targeted by a BDNF-dependent mechanism in the hippocampal CA1 region, and this modulation was shown to be necessary for the enhancement of exocytosis caused by induction of LTP (Tyler et al, 2006).…”