Forebrain overexpression of type 1 adenylyl cyclase promotes molecular stability and behavioral resilience to physical stress.

The ability to cope with stress is essential for emotional stability and mental health. It is also hypothesized that factors promoting resilience to stress may offer treatment strategies for maladaptive disorders such as anxiety and depression. Here, we find that physical restraint reduces the expression of type 1 adenylyl cyclase (Adcy1), a neurospecific synaptic enzyme that positively regulates the cAMP signaling cascade. Conversely, an increase of forebrain Adcy1 expression in transgenic mouse (i.e., Adcy1 (tg) mouse) predisposes individuals to molecular stability and behavioral resilience. Transgenic overexpression of Adcy1 prevents the physical restraint-induced down-regulation of brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY). Further, Adcy1 (tg) mice maintain regular locomotive activity in novelty exploration and voluntary wheel running following physical restraint. Adcy1 (tg) mice show higher corticosterone and lower basal glucocorticoid receptor (GR) expression, along with a higher MR (mineralocorticoid receptor) to GR ratio in the hippocampus. Further, Adcy1 (tg) mice show reduced immobility under acute physical stress conditions in the forced swimming test and are more sensitive to the antidepressant desipramine. Our results demonstrate a novel function of Adcy1 in stress coping and suggest Adcy1 as a potential target to antagonize stress vulnerability and promote antidepressant efficacy.