Abstract
Brain-derived neurotrophic factor (BDNF) is well known as a survival factor during brain development as well as a regulator of adult synaptic plasticity. One potential mechanism to initiate BDNF actions is through its modulation of quantal presynaptic transmitter release. In response to local BDNF application to CA1 pyramidal neurons, the frequency of miniature excitatory postsynaptic currents (mEPSC) increased significantly within 30 seconds; mEPSC amplitude and kinetics were unchanged. This effect was mediated via TrkB receptor activation and required both full intracellular Ca2+ stores as well as extracellular Ca2+. Consistent with a role of Ca2+-permeable plasma membrane channels of the TRPC family, the inhibitor SKF96365 prevented the BDNF-induced increase in mEPSC frequency. Furthermore, labeling presynaptic terminals with amphipathic styryl dyes and then monitoring their post-BDNF destaining in slice cultures by multiphoton excitation microscopy revealed that the increase in frequency of mEPSCs reflects vesicular fusion events. Indeed, BDNF application to CA3-CA1 synapses in TTX rapidly enhanced FM1-43 or FM2-10 destaining with a time course that paralleled the phase of increased mEPSC frequency. We conclude that BDNF increases mEPSC frequency by boosting vesicular fusion through a presynaptic, Ca2+-dependent mechanism involving TrkB receptors, Ca2+ stores, and TRPC channels.
Highlights
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic factor family and is well known as a survival factor and chemoattractant during development of the central nervous system [1]
The present study demonstrates that the BDNF-induced increase in miniature excitatory postsynaptic currents (mEPSC) frequency recorded in hippocampal CA1 pyramidal neurons represents Ca2+-dependent vesicle release from presynaptic terminals
The BDNF-induced increase in mEPSC frequency is prevented by bath application of the tyrosine kinase inhibitor k-252a
Summary
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic factor family and is well known as a survival factor and chemoattractant during development of the central nervous system [1]. It has been shown that BDNF plays a significant role modulating synaptic plasticity in the hippocampus [2,3,4,5,6] These functions include the enhancement of synaptic transmission at excitatory synapses [7] and alterations of dendritic architecture [8], for example, increasing dendritic spine density [9,10,11,12]. Long-term treatment of postnatal hippocampal slice cultures with BDNF increases the frequency of miniature excitatory postsynaptic currents (mEPSCs) recorded from CA1 pyramidal neurons, without affecting their amplitude or kinetics [12] The latter effect of BDNF was specific on a rapidly recyclable pool of vesicles. BDNF selectively enhanced evoked and spontaneous FM1-43 destaining in acute hippocampal slices, but only when presynaptic terminals were dye-loaded with a hyperosmotic shock using sucrose [18], a manipulation that only engages the readily releasable pool of vesicles [19, 20]
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