Exchange protein directly activated by cAMP 2 is required for corticotropin‐releasing hormone‐mediated spine loss

Corticotropin‐releasing hormone is produced in response to acute and chronic stress. Previous studies have shown that activation of the corticotropin‐releasing hormone receptor 1 (CRHR1) by corticotropin‐releasing hormone results in the rapid loss of dendritic spines which correlates with cognitive dysfunction associated with stress. Exchange protein directly activated by cAMP (EPAC2), a guanine nucleotide exchange factor for the small GTPase Rap, plays a critical role in regulating dendritic spine morphology and has been linked with CRHR1 signalling. In this study, we have tested whether EPAC2 links corticotropin‐releasing hormone with dendritic spine remodelling. In primary rat cortical neurons, we show that CRHR1 is highly enriched in the dendritic spines. Furthermore, we find that EPAC2 and CRHR1 co‐localize in cortical neurons and that acute exposure to corticotropin‐releasing hormone induces spine loss. To establish whether EPAC2 was required for corticotropin‐releasing hormone–mediated spine loss, we knocked‐down EPAC2 in cortical neurons using a short hairpin RNA‐mediated approach. In the presence of Epac2 knocked‐down, corticotropin‐releasing hormone was no longer able to induce spine loss. Taken together, our data indicate that EPAC2 is required for the rapid loss of dendritic spines induced by corticotropin‐releasing hormone and may ultimately contribute to responses to acute stress.