BDNF-TrkB Signaling in Efficacy of CA3-CA1 Synapses and Ketamine-Mediated Antidepressant Effects

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2019-11-15

Authors

Lin, Pei-Yi

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Abstract

Brain-derived neurotrophic factor (BDNF) and its high affinity receptor, tropomyosin receptor kinase B (TrkB), regulate synaptic plasticity in the hippocampus. To directly examine the precise synaptic site of BDNF release and the action of TrkB receptors in synaptic plasticity, we used a viral mediated approach to delete BDNF or TrkB selectively in CA1 and CA3 regions of the Schaffer collateral pathway. We first examined the pre and postsynaptic BDNF or TrkB in classic high frequency stimulation (HFS)-induced BDNF-dependent long-term potentiation (LTP). Deletion of BDNF in CA3 or CA1 revealed presynaptic BDNF is involved in LTP induction while postsynaptic BDNF contributes to LTP maintenance. Similarly, loss of pre- or postsynaptic TrkB receptors led to distinct LTP deficits, with presynaptic TrkB required to maintain LTP while postsynaptic TrkB was essential for LTP formation. We also report loss of TrkB in CA3 significantly diminishes release probability uncovering a role for presynaptic TrkB receptors in basal neurotransmission. Taken together, this direct comparison of presynaptic and postsynaptic BDNF-TrkB revealed novel insight into BDNF release and TrkB activation sites in hippocampal LTP. In the subsequent study, we examined BDNF-TrkB signaling in hippocampal CA1 subregion in ketamine-mediated antidepressant effects and synaptic potentiation, a distinctive plasticity process from LTP. Deletion of BDNF or TrkB in CA1 revealed that BDNF-TrkB signaling in CA1 is essential for ketamine-mediated antidepressant effects in both sexes of mice. Loss of BDNF or TrkB in CA1 abolished synaptic potentiation induced by ketamine, indicating the postsynaptic BDNF-TrkB signaling is required for the ketamine-mediated synaptic plasticity. Additionally, postsynaptic TrkB signaling, induced by ketamine, was initiated by a dynamin1-deprendent synaptic machinery in ketamine-mediated synaptic potentiation. These observations suggested the requirement of BDNF-TrkB signaling specific in CA1 in ketamine-induced antidepressant effects and synaptic plasticity, and the involvement of a dynamin1-dependent manner in postsynaptic TrkB signaling triggered by ketamine.

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