Amygdala protein kinase C epsilon regulates corticotropin-releasing factor and anxiety-like behavior

Corticotropin-releasing factor (CRF), its receptors, and signaling pathways that regulate CRF expression and responses are areas of intense investigation for new drugs to treat affective disorders. Here, we report that protein kinase C epsilon (PKC epsilon) null mutant mice, which show reduced anxiety-like behavior, have reduced levels of CRF messenger RNA and peptide in the amygdala. In primary amygdala neurons, a selective PKC epsilon activator, psi epsilon RACK, increased levels of pro-CRF, whereas reducing PKC epsilon levels through RNA interference blocked phorbol ester-stimulated increases in CRF. Local knockdown of amygdala PKC epsilon by RNA interference reduced anxiety-like behavior in wild-type mice. Furthermore, local infusion of CRF into the amygdala of PKC epsilon(-/-) mice increased their anxiety-like behavior. These results are consistent with a novel mechanism of PKC epsilon control over anxiety-like behavior through regulation of CRF in the amygdala.