Advisory Committee Chair
Lucas Pozzo-Miller
Advisory Committee Members
Dale J Benos
J Edwin Blalock
John J Hablitz
Anne B Theibert
Document Type
Dissertation
Date of Award
2008
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Over the years, various roles for neurotrophins have been revealed, being initially described as survival signals for neurons making their initial synaptic contacts in the developing brain. Eventually, it was discovered that these molecules also play important modulatory roles in the adult brain. The work encompassed in this dissertation serves to characterize one particular neurotrophin, brain-derived neurotrophic factor (BDNF), which has been implicated in long-term potentiation (LTP), and its effects at CA3-CA1 synapses in the hippocampus following acute application in vitro. To this end, we have demonstrated the presence of a novel, non-selective cationic current that is initiated by BDNF in hippocampal CA1 pyramidal neurons. This current, IBDNF, is activated when BDNF binds to TrkB receptors on CA1 neurons and requires activation of the PLCγ and PI3K pathways for intracellular Ca2+ mobilization and vesicle exocytosis, respectively. IBDNF is mediated via cell surface membrane TRPC3 channels, assessed using TRPC channel inhibitors and siRNA specifically designed to knock-down TRPC3 mRNA levels. The quantity of cell surface TRPC3 channels was increased via exocytosis of TRPC3-containing vesicles following IBDNF activation. Simultaneous electrophysiology and Ca2+ imaging studies detected an increase in intracellular Ca2+ at proximal dendrites that preceded IBDNF activation, followed by widespread Ca2+ elevations concurrent with membrane depolarization. Activation of TrkB receptors and IP3 receptors, full iii intracellular Ca2+ stores, and the presence of extracellular Ca2+ along with TRPC channels were also required for the BDNF-induced intracellular Ca2+ increase and IBDNF activation. Previously, it has been demonstrated that BDNF causes an increase in dendritic spine density in hippocampal CA1 neurons; interestingly, this effect was nullified upon siRNA knock-down of TRPC3 mRNA and also by TRPC inhibitors, suggesting an important role for TRPC3 channels in BDNF morphogenic functions. A further illustration of this is depicted by our finding that acute application of BDNF to CA3-CA1 synapses rapidly enhances presynaptic quantal transmitter release by Ca2+ mobilization from intracellular stores, a signal further amplified by Ca2+ entry through TRPC channels. Thus, the multifaceted effects of BDNF encompass both the presynapse and the postsynapse at CA3-CA1 synapses in the hippocampus.
Recommended Citation
Amaral, Michelle Dawn, "TRP-Ing Down A TRK: A New Role For Transient Receptor Potential Channels As Novel Mediators Of Brain-Derived Neurotrophic Factor Actions At Both Sides Of The Excitatory Synapse" (2008). All ETDs from UAB. 3656.
https://digitalcommons.library.uab.edu/etd-collection/3656