Activity-dependent BDNF release from mossy fibers evokes a membrane current and Ca2+ elevations mediated by TRPC3 channels in CA3 pyramidal neurons: Implications for Rett syndrome.

LI Y, CALFA G, AMARAL MD, POZZO-MILLER L

Chicago

Congreso; 10th Annual Rett Syndrome Symposium, International Rett Syndrome Foundation (IRSF); 2009

IRSF

The interest in brain-derived neurotrophic factor (BDNF) as an activity-dependent modulator of synapse structure and function in the CNS has intensified in recent years. A myriad of studies have demonstrated that BDNF is a potent modulator of neuronal structure and function in the hippocampus, a brain region involved in learning and memory,as well as in epileptogenesis. We have shown that afferent fiber stimulation evokes a TRPC channel cationic current in CA1 pyramidal neurons that is reminiscent of responses evoked by local application of recombinant BDNF, which requires activation of TrkB receptor, PLCg, IP3 receptors and Ca+2 elevation (Amaral & Pozzo-Miller, J Neurosci 2007). We now extend these studies to area CA3 because the mossy fibers (the axons of dentate gyrus granule cells) express the largest BDNF content in the brain. We performed simultaneous whole-cell recordings and CA+2 imaging in CA3 pyramidal neurons and stimulated their afferent mossy fibers (MFs) using theta-burst patterns (5 burst at 5Hz, each burst having 4 pulses at 100Hz). Theta-burst stimulation of MFs elicited a slowly developing cationic current and Ca+2 signal in CA3 neurons that closely resemble the TRPC3-mediated I BDNF observed in CA1 neurons. As in CA1 neurons, these responses were sensitive to the BDNF scavenger TrkB-IgG and to shRNA-mediated TRPC3 channel knockdown, demonstrating that they reflect release of endogenous BDNF. This form of activity-dependent BDNF release evoked a long-lasting depression of transmitter release at MF-CA3 synapses, lending further credence to the relevance of endogenous BDNF signaling as bioassays of activity-dependent BDNF release in Mecp2 deficient mice. These studies will test whether BDNF release in an underlying mechanism for the pathophysiology of RTT, allowing the in vitro evaluation of potential therapeutic strategies for Mecp2-related neurodevelopmental disorders.