PKCα-deficient mice show altered synaptic signaling and impaired fear extinction

Abstract

Protein kinase C alpha (PKCα), encoded by Prkca, has been implicated in neuronal signaling, plasticity, and memory. Human genetic studies identify PRKCA as a candidate locus relevant to memory and posttraumatic stress disorder (PTSD), but the physiological functions of PKCα remain incompletely defined. Here, we examined the anatomical distribution, signaling function, and behavioral phenotypes associated with constitutive global PKCα deficiency in Prkca-/- mice. PKCα was enriched in forebrain regions, including the hippocampus and prefrontal cortex. It was detected in MAP2-positive neurons and was not detected in GFAP-positive astrocytes. In cultured hippocampal neurons, PKC activation induced redistribution of PKCα to dendritic and membrane-associated compartments, including PSD95-positive postsynaptic sites. PKCα deficiency did not alter gross hippocampal morphology or the basal abundance of major neuronal and synaptic marker proteins, but it reduced basal phosphorylation of pan-PKC, CaMKIIα, and the AMPA receptor subunit GluR1 at Ser831. Male Prkca-/- mice showed impaired hippocampus-dependent spatial memory, increased anxiety-like behavior, and a marked deficit in contextual fear extinction. These findings identify PKCα as part of a signaling program associated with synaptic function and support a role for PKCα-dependent processes in adaptive updating of learned fear.