Description:
<jats:title>Abstract</jats:title><jats:p>Autophagy is a lysosomal degradation pathway that regulates cellular homeostasis. It is constitutively active in neurons and controls the essential steps of neuronal development, leading to its dysfunction in neurodevelopmental disorders. Although mTOR-associated impaired autophagy has previously been reported in neurodevelopmental disorders, there is lack of information about the dysregulation of mTOR-independent autophagy in neurodevelopmental disorders. In this study, we investigated whether the loss of<jats:italic>Epac2,</jats:italic>involved in the mTOR-independent pathway, affects autophagy activity and whether the activity of autophagy is associated with social–behavioral phenotypes in mice with<jats:italic>Epac2</jats:italic>deficiencies<jats:italic>.</jats:italic>We observed an accumulation of autophagosomes and a significant increase in autophagic flux in Epac2-deficient neurons, which had no effect on mTOR activity. Next, we examined whether an increase in autophagic activity contributed to the social behavior exhibited in<jats:italic>Epac2</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>mice. The social recognition deficit observed in<jats:italic>Epac2</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>mice recovered in double transgenic<jats:italic>Epac2</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>:<jats:italic>Atg5</jats:italic><jats:sup>+<jats:italic>/−</jats:italic></jats:sup>mice. Our study suggests that excessive autophagy due to Epac2 deficiencies may contribute to social recognition defects through an mTOR-independent pathway.</jats:p>