PKCα integrates spatiotemporally distinct Ca2+ and autocrine BDNF signaling to facilitate synaptic plasticity

Nature Neuroscience
Lesley A ColganRyohei Yasuda

Abstract

The protein kinase C (PKC) enzymes have long been established as critical for synaptic plasticity. However, it is unknown whether Ca2+-dependent PKC isozymes are activated in dendritic spines during plasticity and, if so, how this synaptic activity is encoded by PKC. Here, using newly developed, isozyme-specific sensors, we demonstrate that classical isozymes are activated to varying degrees and with distinct kinetics. PKCα is activated robustly and rapidly in stimulated spines and is the only isozyme required for structural plasticity. This specificity depends on a PDZ-binding motif present only in PKCα. The activation of PKCα during plasticity requires both NMDA receptor Ca2+ flux and autocrine brain-derived neurotrophic factor (BDNF)-TrkB signaling, two pathways that differ vastly in their spatiotemporal scales of signaling. Our results suggest that, by integrating these signals, PKCα combines a measure of recent, nearby synaptic plasticity with local synaptic input, enabling complex cellular computations such as heterosynaptic facilitation of plasticity necessary for efficient hippocampus-dependent learning.

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Citations

Apr 20, 2019·The Biochemical Journal·Isabel MéridaAntonia Ávila-Flores
Jun 19, 2019·Proceedings of the National Academy of Sciences of the United States of America·Philip J DittmerWilliam A Sather
Jul 18, 2020·PLoS Computational Biology·Mariam OrdyanTerrence Sejnowski
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Aug 17, 2019·Frontiers in Neuroscience·Suk Joon LeeBernardo L Sabatini
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Sep 18, 2020·Current Opinion in Neurobiology·Swathi Shivaram SuratkalJun Nishiyama

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Methods Mentioned

BETA
fluorescence resonance
FRET
light-scattering
biosensors
PCR
transfection
transgenic

Software Mentioned

GraphPad Prism
EthoVision XT
ITRACK
ScanImage
IDOCKSneg
MatLab
IDOCKS
GraphPad

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