Brain-derived neurotrophic factor modulates hippocampal synaptic transmission by increasing N -methyl- d -aspartic acid receptor activity

Abstract

Neurotrophins (NTs) have recently been found to regulate synaptic transmission in the hippocampus. Whole-cell and single-channel recordings from cultured hippocampal neurons revealed a mechanism responsible for enhanced synaptic strength. Specifically, brain-derived neurotrophic factor augmented glutamate-evoked, but not acetylcholine-evoked, currents 3-fold and increased N-methyl-Daspartic acid (NMDA) receptor open probability. Activation of trkB NT receptors was critical, as glutamate currents were not affected by nerve growth factor or NT-3, and increased open probability was prevented by the tyrosine kinase inhibitor K-252a. In addition, the NMDA receptor antagonist MK-801 blocked brain-derived neurotrophic factor enhancement of synaptic transmission, further suggesting that NTs modulate synaptic efficacy via changes in NMDA receptor function.Members of the neurotrophin (NT) gene family play important roles in a wide range of developmental events (1, 2). In addition to promoting neuronal survival and differentiation, we and others have shown that these factors also acutely modulate the efficacy of synaptic transmission (3-9) and play a role in long-term potentiation (LTP;. The specific targets of NT modulation in the synapse have not been identified. In the hippocampus, activation of the trkB neurotrophin receptor by brain-derived neurotrophic factor (BDNF) or NT-4 rapidly increases the amplitude of postsynaptic currents (4, 15). This effect can be blocked by postsynaptic injection of protein kinase inhibitors, suggesting that the specific synaptic proteins targeted by neurotrophin signaling include postsynaptic neurotransmitter receptors, whose function is modulated by phosphorylation (16)(17)(18). In recent studies, we have found that functional trkB receptors are localized to the postsynaptic density (PSD), a synaptic specialization that contains neurotransmitter receptors and second messenger signaling molecules (19). Moreover, we have found that BDNF rapidly and selectively enhances phosphorylation of N-methyl-D-aspartic acid (NMDA) receptor subunits 1 and 2B in isolated hippocampal PSDs (20,21). In the present report, we investigate neurotrophin modulation of neurotransmitter receptors and identify a mechanism by which BDNF acutely modulates hippocampal synaptic function. MATERIALS AND METHODSCell Culture. Hippocampal cultures were grown as described (22). Briefly, hippocampi were obtained from embryonic day 18 Sprague-Dawley rats and cells were plated on poly-D-lysinecoated Petri dishes at a final density of 10 6 cells͞35 mm dish.Cultures were maintained in serum-free medium at 37°C in a 95% air͞5% CO 2 humidified incubator. These cultures contained virtually pure neurons, as judged by neuron-specific enolase immunocytochemistry.Electrophysiological Recordings. Voltage clamp recordings were obtained from pyramidal-type cells after 12-16 days in vitro using standard techniques (23). Cells were recorded in voltage clamp mode and held at a resting potential of Ϫ40 mV to reduce Mg 2ϩ blockade of N...

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