Differential Effects of PACAP-38 on Synaptic Responses in Rat Hippocampal CA1 Region

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP-38) is a member of the vasointestinal polypeptide (VIP)/secretin/glucagon family of neuropeptides for which neuroregulatory functions have been postulated. PACAP-38 receptors are expressed in different brain regions, including hippocampus. In this study, we examined the dose-dependent effects of PACAP-38 on the excitatory postsynaptic field potential (fEPSP) evoked at the Schaffer collateral-CA1 synapse in rat hippocampal slices. Bath application of low dose (0.05 nM) of PACAP-38 induced long-lasting facilitation of the fEPSP. This enhancement was blocked by the cholinergic receptor antagonist atropine and partially by the NMDA receptor antagonist 2-amino-5-phosphonovalerate (APV) and therefore, shares a common mechanism with LTP. In contrast, a high dose (1 µM) of PACAP-38 induced a persistent depression of the fEPSP that was not blocked by antagonists of cholinergic receptors (i.e., atropine and mecamylamine), adenosine receptors (i.e., DCPCX), or glutamatergic NMDA receptors (APV). Intermediate doses (0.1-0.5 µM) of PACAP-38 produced an initial decrease of the fEPSP followed by an enhancement. This decrease was not blocked by atropine whereas the facilitation was. These results show that PACAP-38 modulates CA1 synaptic transmission in a dose-dependent manner and that the peptide interacts with cholinergic and glutamatergic systems.Pituitary adenylate cyclase-activating polypeptide (PACAP-38) is a 38-amino acid peptide that was first isolated from ovine hypothalamus for its ability to stimulate adenylyl cyclase in rat anterior pituitary cells (Arimura 1992). PACAP-38 exhibits high sequence identity with vasoactive intestinal peptide (VIP), distinguishing PACAP-38 as a member of the VIP-secretin-glucagon family of peptides. The aminoacid sequence of PACAP-38 has been remarkably conserved during evolution, suggesting that PACAP-38 regulates important physiological functions (Arimura 1992;Masuo et al. 1993). Two receptors for PACAP-38 have been identified: type I receptors, which are positively coupled to adenylyl cyclase and phospholipase C, and type II receptors, which have only been linked to adenylyl cyclase (Spengler et al. 1993). PACAP-38 receptors are mainly distributed in the central nervous system including the hippocampus (Masuo et al. 1992(Masuo et al. , 1993.PACAP-38 modulates synaptic activity in several neuronal regions. For example, PACAP-38 enhances in a dosedependent manner the spontaneous release of acetylcholine (ACh) from septal cholinergic fibers in the dorsal hippocampus (Masuo et al. 1993). An excitatory action of PACAP-38 on glutamatergic N-methyl-D-aspartate (NMDA) receptors has also been reported in cortical neurons (Martin et al. 1995;Stella and Magistretti 1996;Liu and Madsen 1997) and in sympathetic preganglionic neurons of neonatal rat (Lai et al. 1997;Wu and Dun 1997). In addition, a high concentration of PACAP-38 (1-3 µM) induces a long-lasting depression of the field excitatory postsynaptic potential (fEPSP) at hippocampal ...

Regulation of AMPA receptor phosphorylation by the neuropeptide PACAP38

“…It has been reported that a low dose of PACAP38 may influence synaptic transmission through the regulation of NMDARs (20). NMDAR activation has also been shown to result in GluA1 T840 dephosphorylation (16,17).…”

“…In contrast, the GluA1 T840 site is less well characterized. PKC, calcium/calmodulin-dependent protein kinase II, protein phosphatase 1/2A (PP1/PP2A), and NMDAR activity have been reported to regulate GluA1 T840 phosphorylation (15-17).GluA1 T840 phosphorylation has also been found to enhance channel conductance (18).PACAP38 (pituitary adenylate cyclase activating polypeptide 38) is a neuropeptide that has been shown to regulate hippocampal CA1 synaptic strength (19)(20)(21)(22). PACAP38 can bind to and activate three different G protein coupled receptors, the PAC1, VPAC1, and VPAC2 receptors, which can lead to elevated cyclic AMP and Ca 2+ levels, and activation of phospholipase C and phospholipase D (23).…”

“…PACAP38 can bind to and activate three different G protein coupled receptors, the PAC1, VPAC1, and VPAC2 receptors, which can lead to elevated cyclic AMP and Ca 2+ levels, and activation of phospholipase C and phospholipase D (23). In the hippocampus, PACAP38 stimulation has been shown to alter synaptic strength (19)(20)(21)(22) and AMPAR excitatory postsynaptic currents (EPSCs) (24) and to reduce GluA1 synaptic localization (25). PACAP knockout mice are impaired in contextual fear conditioning and novel object recognition (26), and PAC1 receptor knockouts exhibit impaired contextual fear conditioning (27).…”

“…PACAP38 (pituitary adenylate cyclase activating polypeptide 38) is a neuropeptide that has been shown to regulate hippocampal CA1 synaptic strength (19)(20)(21)(22). PACAP38 can bind to and activate three different G protein coupled receptors, the PAC1, VPAC1, and VPAC2 receptors, which can lead to elevated cyclic AMP and Ca 2+ levels, and activation of phospholipase C and phospholipase D (23).…”

The neuropeptide PACAP38 induces dendritic spine remodeling through ADAM10/N-Cadherin signaling pathway

“…By contrast, another study showed that the application of PACAP38 enhanced AMPA-evoked currents (Michel et al, 2006). PACAP38 has been also shown to induce a form of long-term depression (LTD) in hippocampal neurons that requires interaction of AMPA receptor subunits with scaffolding proteins (Kondo et al 1997;Roberto et al 2001;Ster et al, 2009), thus validating its role in learning and memory. This has been further confirmed by the use of transgenic animals (Yang et al, 2010).…”