Pituitary adenylate cyclase activating polypeptide induces long-term, transcription-dependent plasticity and...

Pituitary adenylate cyclase activating polypeptide (PACAP) is a multifunctional neuropeptide, widely expressed in the nervous system (Vaudry et al., 2009; Starr and Margiotta, 2016). At neuronal synapses where transmission is mediated by nicotinic acetylcholine receptors (nAChRs) transient PACAP exposure increases the frequency and amplitude (F_S and A_S) of spontaneous excitatory postsynaptic currents (sEPSCs) within minutes. This short-term (ST) plasticity requires high-affinity PACAP receptor (PAC₁R) signaling via adenylate cyclase (AC), cyclic AMP (cAMP), Protein kinase A (PKA) and obligatory nAChR-dependent stimulation of nitric oxide (NO) synthesis to retrogradely increase presynaptic ACh release (Pugh et al., 2010; Jayakar et al., 2014). Remarkably, synaptic changes persist 48h after transient PACAP exposure, featuring a similar increase in F_S and an even larger increase in A_S. Pharmacological studies reveal that this long-term (LT) plasticity requires PACAP/PAC₁R signaling via AC and cAMP, but unlike ST plasticity, Phospholipase-C and new gene transcription are also necessary, whereas PKA, nAChR, impulse and NO synthase (NOS1) activities are dispensable. In accord with the increases in F_S and A_S characterizing LT plasticity, miniature EPSC (mEPSC) frequency, ACh release (quantal content), and mEPSC amplitude (quantal size) all increased in parallel. Consistent with these functional changes, imaging studies reveal that LT, but not ST, PACAP-induced plasticity is accompanied by increases in presynaptic terminal size, postsynaptic nAChR cluster size and density, and the size and density of co-localized pre- and post-synpatic sites. Thus PACAP/PAC₁R signaling induces mechanistically distinct forms of synaptic plasticity, with a ST form arising from acute, membrane-delimited processes, and a LT form arising from transcription-dependent alterations in the function and structural arrangement of pre- and post-synaptic components.