The traditional roles of cAMP-PKA signaling in modulating neurotransmission and neuroplasticity. (a) cAMP-PKA signaling can enhance transmitter release (e.g., glutamate release) from the presynaptic terminal by priming vesicles for release. (b) cAMP-PKA signaling is needed for late-stage LTP in hippocampal neurons. These synapses generally contain AMPAR and NMDAR-NR2A subunits, whereas NMDAR-NR2Bs are found extrasynaptically. This process can involve internal calcium release from a spine apparatus in some synapses. Sufficient activation of PKA can lead to phosphorylation of CREB and transcriptional changes that can lead to spine enlargement (an immature, thin learning spine becomes a mushroom spine) and/or enlargement and stabilization of the PSD. Abbreviations: AC, adenylyl cyclase; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element–binding protein; IP3R, inositol 1,4,5-trisphosphate receptor; LTP, long-term potentiation; NMDA, N-methyl-d-aspartate; NMDAR, NMDA receptor; pCREB, phosphorylated CREB; PKA, protein kinase A; PSD, postsynaptic density.