An enriched environment ameliorates memory impairments in PACAP-deficient mice

Takuma, Kazuhiro; Maeda, Yuko; Ago, Yukio; Ishihama, Toshihiro; Takemoto, Kosuke; Nakagawa, Akira; Shintani, Norihito; Hashimoto, Hitoshi; Baba, Akemichi; Matsuda, Takehisa

doi:10.1016/j.bbr.2014.07.005

Cited by 39 publications

(34 citation statements)

References 36 publications

(51 reference statements)

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“…Differences in age, strain, and organ-specific mechanisms can also explain the discrepancy between our findings and those of Girard et al [29]. Another study suggested that the compensatory mechanisms may be very complex, and not due to one molecule, as rearing PACAP-KO mice in an enriched environment could increase the protein levels of the NMDA receptor NR2B subunit, phospho-ERK, phospho-CaMKII, and brain-derived neurotrophic factor, resulting in the amelioration of memory impairments shown in the PACAP-KO mice [30]. The vascular relaxation to PACAP1-38 is reduced with aging, which is similar to our previous observations in old rats [11].…”

Section: Discussioncontrasting

confidence: 56%

Aging-Induced Modulation of Pituitary Adenylate Cyclase-Activating Peptide- and Vasoactive Intestinal Peptide-Induced Vasomotor Responses in the Arteries of Mice

Ivić¹,

Solymár

Fülöp³

et al. 2017

J Vasc Res

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Pituitary adenylate cyclase-activating peptide (PACAP; 1-38 and 1-27) and vasoactive intestinal peptide (VIP) are related neuropeptides of the secretin/glucagon family. Overlapping signaling through G-protein-coupled receptors mediates their vasomotor activity. We previously showed that PACAP deficiency (PACAP-KO) shifts the mechanisms of vascular response and maintains arterial relaxation through the VIP backup mechanism and (mainly) its VPAC1R, but their age-dependent modulation is still unknown. We hypothesized that backup mechanisms exist, which maintain the vasomotor activity of these peptides also in older age. Thus, we investigated the effects of exogenous VIP and PACAP peptides in isolated carotid arteries of 2- and 15-month-old wild-type (WT) and PACAP-KO mice. All peptides induced relaxation in the arteries of young WT mice, whereas in young PACAP-KO mice PACAP1-27 and VIP, but not PACAP1-38, induced relaxation. Unlike VIP, PACAP-induced vasomotor responses were reduced in aging WT mice. However, in the arteries of aging PACAP-KO mice, PACAP1-27- and VIP-induced responses were reduced, but PACAP1-38 showed a greater vasomotor response compared to that of young PACAP-KO animals. There were no significant differences between the vasomotor responses of aging WT and PACAP-KO mice. Our data suggest that, in the absence of PACAP both in young and old ages, the vascular response is mediated through backup mechanisms, most likely VIP, maintaining proper vascular relaxation in aging-induced PACAP insufficiency.

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Section: Discussioncontrasting

confidence: 56%

Aging-Induced Modulation of Pituitary Adenylate Cyclase-Activating Peptide- and Vasoactive Intestinal Peptide-Induced Vasomotor Responses in the Arteries of Mice

Ivić¹,

Solymár

Fülöp³

et al. 2017

J Vasc Res

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“…Likewise it will be interesting to see if changes in synaptic strength occur through alterations in AMPAR trafficking or conductance. Finally, these findings suggest that deficits in AMPAR phosphorylation may underlie the role of PACAP38 and the PAC1 receptor in PTSD and fear memory (26,27,29).…”

Section: Discussionmentioning

confidence: 99%

“…In humans, a sex-specific association between a single-nucleotide polymorphism in a PACAP38 receptor, the PAC1 receptor, and posttraumatic stress disorder (PTSD) has been reported (29). Moreover, the PAC1 receptor knockout exhibits impaired contextual fear conditioning (27), and the PACAP38 knockout exhibit impaired contextual fear and novel object recognition (26).…”

Section: Discussionmentioning

confidence: 99%

“…Maxadillan and (Lys15, Arg16,Leu27)-VIP(1-7)-GRF (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), abbreviated as K,R,L-VIP-GRF, were purchased from Bachem. PACAP38, Bay 55-9837, Go6983, D-APV, and H89 were purchased from Tocris.…”

Section: Methodsmentioning

confidence: 99%

“…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). Given the ability of PACAP38 to regulate basal synaptic transmission and AMPAR EPSCs (24), we hypothesized that PACAP38 stimulation could alter AMPAR phosphorylation levels.…”

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confidence: 99%

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Regulation of AMPA receptor phosphorylation by the neuropeptide PACAP38

Toda

Huganir

2015

Proc. Natl. Acad. Sci. U.S.A.

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Dynamic changes in synaptic strength are thought to be critical for higher brain function such as learning and memory. Alterations in synaptic strength can result from modulation of AMPA receptor (AMPAR) function and trafficking to synaptic sites. The phosphorylation state of AMPAR subunits is one mechanism by which cells regulate receptor function and trafficking. Receptor phosphorylation is in turn regulated by extracellular signals; these include neuronal activity, neuropeptides, and neuromodulators such as dopamine and norepinephrine (NE). Although numerous studies have reported that the neuropeptide pituitary adenylate cyclase activating polypeptide 38 (PACAP38) alters hippocampal CA1 synaptic strength and GluA1 synaptic localization, its effect on AMPAR phosphorylation state has not been explored. We determined that PACAP38 stimulation of hippocampal cultures increased phosphorylation of S845, and decreased phosphorylation of T840 on the GluA1 AMPAR subunit. Increases in GluA1 S845 phosphorylation primarily occurred via PAC1 and VPAC2 receptor activation, whereas a reduction in GluA1 T840 phosphorylation was largely driven by PAC1 receptor activation and to a lesser extent by VPAC1 and VPAC2 receptor activation. GluA1 S845 phosphorylation could be blocked by a PKA inhibitor, and GluA1 T840 dephosphorylation could be blocked by a protein phosphatase 1/2A (PP1/PP2A) inhibitor and was partly blocked by a NMDA receptor (NMDAR) antagonist. These results demonstrate that the neuropeptide PACAP38 inversely regulates the phosphorylation of two distinct sites on GluA1 and may play an important role modulating AMPAR function and synaptic plasticity in the brain.PACAP38 | AMPA receptor phosphorylation | synaptic transmission A MPA-type glutamate receptors (AMPARs) are a tetrameric assembly composed of the GluA1, 2, 3, or 4 subunits. Within the adult hippocampus, receptors consist of primarily GluA1/2 and GluA2/3 complexes (1). Because AMPARs conduct the majority of excitatory transmission in the brain, modulation of AMPAR synaptic transmission is a powerful tool by which the cell can regulate synaptic strength and cell firing. Furthermore, it is hypothesized that complex behaviors such as learning, memory, and drug addiction involve alterations in synaptic strength (2, 3).The cell can regulate synaptic strength through changes in AMPAR conductance, trafficking, and tethering at synaptic sites. Such changes can be achieved through alterations in AMPAR expression, binding partners, and posttranslational modifications (4). A number of GluA1 and GluA2 phosphorylation sites have been proposed to play a role in AMPAR trafficking and synaptic plasticity. GluA1 S845 and T840 are two phosphorylation sites particularly relevant to this study. GluA1 S845 is phosphorylated by PKA and cGMP-dependent protein kinase II (5, 6). Its phosphorylation levels are regulated by NMDA receptors (NMDARs) (7), β-adrenergic receptors (8, 9), and muscarinic cholinergic receptors (9), and during homeostatic scaling (10), long-term depression (LTD...

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Genomic Regulation of the PACAP Receptor, PAC1, and Implications for Psychiatric Disease

Mercer

Ressler

2016

Epigenetics and Neuroendocrinology

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An enriched environment ameliorates memory impairments in PACAP-deficient mice

Cited by 39 publications

References 36 publications

Aging-Induced Modulation of Pituitary Adenylate Cyclase-Activating Peptide- and Vasoactive Intestinal Peptide-Induced Vasomotor Responses in the Arteries of Mice

Aging-Induced Modulation of Pituitary Adenylate Cyclase-Activating Peptide- and Vasoactive Intestinal Peptide-Induced Vasomotor Responses in the Arteries of Mice

Regulation of AMPA receptor phosphorylation by the neuropeptide PACAP38

Genomic Regulation of the PACAP Receptor, PAC1, and Implications for Psychiatric Disease

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