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.