Long-term memory formation depends on the expression of immediate early genes (IEGs). Their expression, which is induced by synaptic activation, is mainly regulated by the 3′,5′-cyclic AMP (cAMP)-dependent protein kinase/cAMP response element binding protein (cAMP-dependent protein kinase (PKA)/ cAMP response element binding (CREB)) signaling pathway. Synaptic activation being highly energy demanding, neurons must maintain their energetic homeostasis in order to successfully induce long-term memory formation. In this context, we previously demonstrated that the expression of IEGs required the activation of AMP-activated protein kinase (AMPK) to sustain the energetic requirements linked to synaptic transmission. Here, we sought to determine the molecular mechanisms by which AMPK regulates the expression of IEGs. To this end, we assessed the involvement of AMPK in the regulation of pathways involved in the expression of IEGs upon synaptic activation in differentiated primary neurons. Our data demonstrated that AMPK regulated IEGs transcription via the PKA/CREB pathway, which relied on the activity of the soluble adenylyl cyclase. Our data highlight the interplay between AMPK and PKA/CREB signaling pathways that allows synaptic activation to be transduced into the expression of IEGs, thus exemplifying how learning and memory mechanisms are under metabolic control.