Differential Activity-Dependent Secretion of Brain-Derived Neurotrophic Factor from Axon and Dendrite

Abstract

Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival and differentiation during development and for synaptic function and plasticity in the mature brain. BDNF-containing vesicles are widely distributed and bidirectionally transported in neurons, and secreted BDNF can act on both presynaptic and postsynaptic cells. Activity-dependent BDNF secretion from neuronal cultures has been reported, but it remains unknown where the primary site of BDNF secretion is and whether neuronal activity can trigger BDNF secretion from axons and dendrites with equal efficacy. Using BDNF fused with pH-sensitive green fluorescent protein to visualize BDNF secretion, we found that BDNF-containing vesicles exhibited markedly different properties of activity-dependent exocytic fusion at the axon and dendrite of cultured hippocampal neurons. Brief spiking activity triggered a transient fusion pore opening, followed by immediate retrieval of vesicles without dilation of the fusion pore, resulting in very little BDNF secretion at the axon. On the contrary, the same brief spiking activity induced "full-collapse" vesicle fusion and substantial BDNF secretion at the dendrite. However, full vesicular fusion with BDNF secretion could occur at the axon when the neuron was stimulated by prolonged high-frequency activity, a condition neurons may encounter during epileptic discharge. Thus, activity-dependent axonal secretion of BDNF is highly restricted as a result of incomplete fusion of BDNF-containing vesicles, and normal neural activity induces BDNF secretion from dendrites, consistent with the BDNF function as a retrograde factor. Our study also revealed a novel mechanism by which differential exocytosis of BDNF-containing vesicles may regulate BDNF-TrkB signaling between connected neurons.

Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin

“…We have thus focused our attention on BDNF-QD secretion at the dendrite. Studies using cultured hippocampal neurons expressing fluorescently tagged-BDNF have shown BDNF secretion at both axons and dendrites (45,46). However, BDNF and its propeptide have been found in presynaptic dense core vesicles, but not in the postsynaptic dendrites of the adult mouse hippocampus (6), suggesting an anterograde mode of action of BDNF.…”

Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

“…Moreover, hippocampal slices from BDNF heterozygous mice displayed a significant decline of CAF LTP compared with WT. Previous experimental findings indicate that BDNF may be released at both pre‐ and postsynaptic levels (Lessmann & Brigadski 2009; Matsuda et al 2009; Edelmann et al 2014) and it is known that BDNF can significantly affect PPF (Kang & Schuman 1995). In our experiments, caffeine perfusion induced a significant change in PPF response suggesting an enhancement of the neurotransmitter release.…”

Calcium-dependent activator protein for secretion 2 (CAPS2) promotes BDNF secretion and is critical for the development of GABAergic interneuron network

“…It also exhibits a neurotrophic action on the development of GABAergic interneurons and their networks in the cerebral cortex (13)(14)(15) and hippocampus (16,17). BDNF is secreted from DCV-like secretory vesicles from neuronal dendrites and axons (18). Together with CAPS2, synaptotagmin-IV also controls BDNF secretion, although these two proteins act in opposite ways: CAPS2 promotes secretion (7,8), whereas synaptotagmin-IV inhibits secretion (19).…”