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.
PKCα integrates spatiotemporally distinct Ca2+ and autocrine BDNF signaling to facilitate synaptic plasticity
Model of integration of TrkB and calcium signals to induce PKCα activation in paired and unpaired subthreshold stimulations. A subthreshold stimulus that was unable to induce plasticity was given alone (unpaired) or after a nearby plasticity-inducing stimulation (paired). Unpaired, the stimulus could not activate PKCα or induce plasticity. However, when paired with recent plasticity in a nearby spine, which induces a long-lasting, spreading TrkB activity, this same subthreshold stimulus led to PKCα activation and plasticity.
Max Planck Florida Institute for Neuroscience
