PKCα integrates spatiotemporally distinct Ca(2+) and autocrine BDNF signaling to facilitate synaptic plasticity

The Protein Kinase C (PKC) enzymes have long been established as critical for synaptic plasticity. However, it is unknown whether Ca(2+)-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 classic isozymes are activated to varying degrees and with unique 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 domain present only in PKCα. The activation of PKCα during plasticity requires both NMDAR Ca(2+)-flux and autocrine 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 hippocampal-dependent learning.