Activity-Dependent Release of Endogenous BDNF From Mossy Fibers Evokes a TRPC3 Current and Ca²⁺Elevations in CA3 Pyramidal Neurons

Abstract

Multiple studies have demonstrated that brain-derived neurotrophic factor (BDNF) is a potent modulator of neuronal structure and function in the hippocampus. However, the majority of studies to date have relied on the application of recombinant BDNF. We herein report that endogenous BDNF, released via theta burst stimulation of mossy fibers (MF), elicits a slowly developing cationic current and intracellular Ca 2ϩ elevations in CA3 pyramidal neurons with the same pharmacological profile of the transient receptor potential canonical 3 (TRPC3)-mediated I BDNF activated in CA1 neurons by brief localized applications of recombinant BDNF. Indeed, sensitivity to both the extracellular BDNF scavenger tropomyosin-related kinase B (TrkB)-IgG and small hairpin interference RNA-mediated TRPC3 channel knockdown confirms the identity of this conductance as such, henceforth-denoted MF-I BDNF . Consistent with such activity-dependent release of BDNF, these MF-I BDNF responses were insensitive to manipulations of extracellular Zn 2ϩ concentration. Brief theta burst stimulation of MFs induced a long-lasting depression in the amplitude of excitatory postsynaptic currents (EPSCs) mediated by both AMPA and N-methyl-D-aspartate (NMDA) receptors without changes in the NMDA receptor/AMPA receptor ratio, suggesting a reduction in neurotransmitter release. This depression of NMDAR-mediated EPSCs required activitydependent release of endogenous BDNF from MFs and activation of Trk receptors, as it was sensitive to the extracellular BDNF scavenger TrkB-IgG and the tyrosine kinase inhibitor k-252b. These results uncovered the most immediate response to endogenously releasednative-BDNF in hippocampal neurons and lend further credence to the relevance of BDNF signaling for synaptic function in the hippocampus.

Neurotrophin-mediated dendrite-to-nucleus signaling revealed by microfluidic compartmentalization of dendrites

“…It will be important to image BDNF-TrkB endosome trafficking from dendrites to the cell body, and to determine if these signaling endosomes contribute to BDNF-mediated changes in synaptic plasticity in a physiological context. Previous studies have shown that theta-burst stimulation induces the release of endogenous BDNF from mossy fibers, as well as Schaffer collaterals onto the dendrites of CA3 and CA1 pyramidal neurons, respectively, and this mediates long-lasting changes in potentiation or depression (3,48,6,49). Moreover, a recent study demonstrated that release of BDNF from cortical axons onto dendrites of medium spiny neurons in the dorsal striatum induced postsynaptic LTP (50).…”

Mechanisms of BDNF regulation in asthmatic airway smooth muscle

“…Here, BDNF has been shown to induce Ca 2ϩ elevation via TRPC3, and BDNF activity (i.e., excitatory postsynaptic neurotransmission and synaptic vesicle fusion), which is mediated by TrkB, seems to require intracellular and extracellular Ca 2ϩ (3,28). TRPC3 is also necessary for activity-dependent release of BDNF, and for BDNF function, via a nonselective cationic current, during development (4,25). TRPC6 is involved in BDNF processing (from its precursor to mature BDNF) in retinal ganglion cells (47).…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…TRPC3 can form homomeric channels but also heteromerizes with TRPC1/TRPC4/TRPC5/TRPC6/ TRPC7 in some cell types (Strübing et al, 2003;Dietrich et al, 2005a). TRPC3 is highly expressed in endothelial cells (in caveolae) (Adebiyi et al, 2011;Senadheera et al, 2012), in the brain (e.g., cerebellum, cortex, substantia nigra, and hippocampus) both in neurons and glia Roedding et al, 2009;Li et al, 2010;Mitsumura et al, 2011;Zhou and Lee, 2011), in the pituitary gland, smooth muscle, and cardiac muscle cells (Watanabe et al, 2008;Gonzalez-Cobos and Trebak, 2010), as well as in sensory organs such as the cochlea (Tadros et al, 2010).…”