Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors.

Abstract

Although neurotrophins are primarily associated with long-term effects on neuronal survival and differentiation, recent studies have shown that acute changes in synaptic transmission can also be produced. In the hippocampus, an area critically involved in learning and memory, we have found that brain-derived neurotrophic factor (BDNF) rapidly enhanced synaptic efficacy through a previously unreported mechanism-increased postsynaptic responsiveness via a phosphorylation-dependent pathway. Within minutes of BDNF application to cultured hippocampal neurons, spontaneous firing rate was dramatically increased, as were the frequency and amplitude of excitatory postsynaptic currents. The increased frequency of postsynaptic currents resulted from the change in presynaptic firing. However, the increased amplitude was postsynaptic in origin because it was selectively blocked by intracellular injection of the tyrosine kinase receptor (Ntrk2/TrkB) inhibitor K-252a and potentiated by injection of the phosphatase inhibitor okadaic acid. These results suggest a role for BDNF in the modulation of synaptic transmission in the hippocampus.Neurotrophins are important regulators of the survival, development, and differentiation of multiple neuronal populations (1-3). These effects generally occur over the course of hours or even days. Recently, evidence has accumulated that neurotrophins can also modulate transmitter release and synaptic transmission (4-8). Such effects could underly a role for these factors in synaptic plasticity. The potential effects of neurotrophins on synaptic transmission in the hippocampus were studied with primary cultures of embryonic hippocampal neurons. We report that brain-derived neurotrophic factor (BDNF) rapidly enhanced the strength of synaptic connections in these neurons. Both the amplitude and the frequency of excitatory postsynaptic currents (EPSCs) were increased within 2-3 min of neurotrophin application. Moreover, the potentiation of synaptic current amplitude occurred via a previously undescribed postsynaptic mechanism in which BDNF increased the responsiveness of the postsynaptic neuron to the excitatory input. These results indicate a previously unreported role for this neurotrophin in the hippocampus. MATERIALS AND METHODS

Single-Cell Characterization of Retrograde Signaling by Brain-Derived Neurotrophic Factor

“…For the time-course analysis, a response was defined as a sustained increase in activity at least 2 SEs over baseline. Consistent with our previous work (Levine et al, 1995), the majority of recorded neurons under control conditions responded to depolarization of Ϫ40 mV with an increase in mEPSC frequency. The small number of cells that did not respond were assumed to be of a different neuronal subtype and were not included in the analysis.…”

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).…”

The Role of Brain-Derived Neurotrophic Factor Receptors in the Mature Hippocampus: Modulation of Long-Term Potentiation through a Presynaptic Mechanism involving TrkB

“…Using cultured hippocampal neurons as a model system, BDNF has been shown to enhance transmitter release via a mechanism inhibitable by expression of a dominant negative variant of TrkB in presynaptic cells (Li et al, 1998), suggesting a presynaptic locus via the receptor TrkB. In contrast, BDNF has been shown by different groups to enhance not only presynaptic transmitter release but also postsynaptic transmission through NMDA channels in cultured hippocampal neurons (Levine et al, 1995(Levine et al, , 1998. Interneurons are also a potential locus for BDNF action, because BDNF deficiency clearly inhibits the differentiation of these neurons (Jones et al, 1994), and acute application of BDNF has been shown to decrease inhibition in slices from adult animals (Tanaka et al, 1997;Frerking et al, 1998).…”