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

Nat Neurosci. 2018 Aug;21(8):1027-1037. doi: 10.1038/s41593-018-0184-3. Epub 2018 Jul 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autocrine Communication / genetics
  • Autocrine Communication / physiology*
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / physiology*
  • Calcium Signaling / genetics
  • Calcium Signaling / physiology*
  • Dendritic Spines
  • Enzyme Activation
  • Hippocampus / physiology
  • Isoenzymes
  • Kinetics
  • Learning / physiology
  • Male
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuronal Plasticity / physiology*
  • Protein Kinase C-alpha / genetics
  • Protein Kinase C-alpha / physiology*
  • Receptors, N-Methyl-D-Aspartate / metabolism


  • Bdnf protein, mouse
  • Brain-Derived Neurotrophic Factor
  • Isoenzymes
  • Receptors, N-Methyl-D-Aspartate
  • Prkca protein, mouse
  • Protein Kinase C-alpha