The Involvement of PACAP/VIP System in the Synaptic Transmission in the Hippocampus

Yang, Kai; Liu, Gang; Jackson, Michael; MacDonald, John F.

doi:10.1007/s12031-010-9372-7

Cited by 49 publications

(48 citation statements)

References 58 publications

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“…Rodent studies of PACAP show that it has neurotrophic effects (24,26) and may facilitate synaptic plasticity (25,27). Plasticity in the amygdala and hippocampus is crucial to multiple forms of memory, playing a central role in reinforcement learning and declarative memory.…”

Section: Discussionmentioning

confidence: 99%

“…We also examined the hippocampus, another brain region that plays a central role in PTSD (22), where PACAP binding sites are particularly dense (23) and where PACAP has been shown to act in a neuroprotective or neurotrophic manner (24)(25)(26) and may facilitate synaptic plasticity (25,27). We predicted that individuals with the risk polymorphism would show exaggerated amygdala responses to threat stimuli and decreased functional connectivity between the amygdala and the hippocampus and medial prefrontal cortex, regions that regulate amygdala reactivity (28,29).…”

Section: Significancementioning

confidence: 99%

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PACAP receptor gene polymorphism impacts fear responses in the amygdala and hippocampus

Stevens

Almli

Fani

et al. 2014

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

122

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We have recently found higher circulating levels of pituitary adenylate cyclase-activating polypeptide (PACAP) associated with posttraumatic stress disorder (PTSD) symptoms in a highly traumatized cohort of women but not men. Furthermore, a single nucleotide polymorphism in the PACAP receptor gene ADCYAP1R1, adenylate cyclase activating polypeptide 1 receptor type 1, was associated with individual differences in PTSD symptoms and psychophysiological markers of fear and anxiety. The current study outlines an investigation of individual differences in brain function associated with ADCYAP1R1 genotype. Forty-nine women who had experienced moderate to high levels of lifetime trauma participated in a functional MRI task involving passive viewing of threatening and neutral face stimuli. Analyses focused on the amygdala and hippocampus, regions that play central roles in the pathophysiology of PTSD and are known to have high densities of PACAP receptors. The risk genotype was associated with increased reactivity of the amygdala and hippocampus to threat stimuli and decreased functional connectivity between the amygdala and hippocampus. The findings indicate that the PACAP system modulates medial temporal lobe function in humans. Individual differences in ADCYAP1R1 genotype may contribute to dysregulated fear circuitry known to play a central role in PTSD and other anxiety disorders.fMRI | emotion | intermediate phenotype | single nucleotide polymorphism P osttraumatic stress disorder (PTSD) is an anxiety disorder estimated to affect 7% of the population (1), with symptoms that are highly debilitating and associated with a range of major physical health conditions (2, 3). PTSD disproportionally affects women over men (1, 4), and mechanisms for this sex difference have not yet been defined. We recently identified a single nucleotidepolymorphism (SNP) in the gene coding for the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor (ADCYAP1R1, adenylate cyclase activating polypeptide 1 receptor type 1) that predicts PTSD in women and not men (5-9). This SNP, rs2267735, is located on a canonical estrogen response element, indicating that estrogen levels may influence expression of the receptor. The ADCYAP1R1 polymorphism has been shown to predict exaggerated arousal responses characteristic of PTSD in autonomic psychophysiology (5, 10), but no study has yet examined the extent to which this polymorphism influences fear responses in the human brain. The current study tests the hypothesis that ADCYAP1R1 polymorphism influences brain regions that underlie emotional arousal, using functional MRI (fMRI) in a sample of women who have experienced civilian trauma.PTSD symptom clusters include hyperarousal, reexperiencing, avoidance, and numbing (11). Recently, evidence has accumulated to support the idea that hyperarousal is predictive of PTSD after trauma, whereas other symptoms are products of the disorder (12). In particular, pretrauma reactivity of the amygdalaa brain region responsible for coordinating and mainta...

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

PACAP receptor gene polymorphism impacts fear responses in the amygdala and hippocampus

Stevens

Almli

Fani

et al. 2014

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

122

View full text Add to dashboard Cite

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“…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). Nonetheless, the mechanism by which PACAP38-dependent signaling can modify AMPA receptors remains almost unknown and no information is available on the effect of PACAP38 on AMPA receptor subunit localization at the synapse.…”

Section: Introductionmentioning

confidence: 91%

“…It has been shown that PACAP38 modulates a variety of signaling pathways within the excitatory glutamatergic synapse (MacDonald et al, 2005;Yang et al, 2009;Yang et al, 2010), ranging from activation of different protein kinases, i.e. protein kinase A (PKA) and the mitogen-activated protein (MAP) kinase to the mobilization of calcium (Harmar et al, 1998;Vaudry et al, 2000;Kojro et al, 2006;Ohnishi et al, 2008;Yang et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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

Gardoni

Saraceno

Malinverno

et al. 2012

Journal of Cell Science

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SummaryThe neuropeptide pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) has been implicated in the induction of synaptic plasticity at the excitatory glutamatergic synapse. In particular, recent studies have shown that it is involved in the regulation of Nmethyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation. Here we demonstrate the effect of PACAP38 on the modulation of dendritic spine morphology through a disintegrin and metalloproteinase 10 (ADAM10)-N-cadherin-AMPA receptor signaling pathway. Treatment of primary hippocampal neurons with PACAP38 induced an accumulation of ADAM10 at the postsynaptic membrane. This event led to a significant decrease of dendritic spine head width and to a concomitant reduction of GluR1 colocalization with postsynaptic markers. The PACAP38-induced effect on dendritic spine head width was prevented by either treatment with the ADAM10-specific inhibitor or transfection of a cleavage-defective N-cadherin construct mutated in the ADAM10 cleavage site. Overall, our findings reveal that PACAP38 is involved in the modulation of dendritic spine morphology in hippocampal neurons, and assign to the ADAM10-N-cadherin signaling pathway a crucial role in this modification of the excitatory glutamatergic synapse.

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“…Pentylenetetrazol-induced seizures resulted in short term decrease in the level of VIP [57,201]. VIP has an overall excitatory action on synaptic transmission in the hippocampus [202], in which the cAMP-mediated activation of NMDA receptor plays a role [203]. Still, VIP was neuroprotective in some models of neurodegeneration including neuroinflammation [204] and beta-amyloidinduced neurodegeneration [205] providing the possible neuroprotective role in epileptic sclerosis.…”

Section: Vasoactive Intestinal Peptidementioning

confidence: 99%

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Dobolyi¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre-and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have been implicated in epilepsy and many of them are considered to have endogenous neuroprotective actions. Neuropeptides, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic substances. Hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin-releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Oral application of neuropeptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of neuropeptides within the central nervous system will also be discussed.

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The Involvement of PACAP/VIP System in the Synaptic Transmission in the Hippocampus

Cited by 49 publications

References 58 publications

PACAP receptor gene polymorphism impacts fear responses in the amygdala and hippocampus

PACAP receptor gene polymorphism impacts fear responses in the amygdala and hippocampus

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

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

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