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

Gardoni, Fabrizio; Saraceno, Claudia; Malinverno, Matteo; Marcello, Elena; Verpelli, Chiara; Sala, Carlo; Luca, Monica Di

doi:10.1242/jcs.097576

Cited by 33 publications

(31 citation statements)

References 25 publications

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“…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%

“…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).…”

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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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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Regulation of AMPA receptor phosphorylation by the neuropeptide PACAP38

Toda

Huganir

2015

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

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“…In fact, ADAM10 cleavage of synaptic adhesion molecules may allow the activated synapse to rapidly modulate the spine size during induction of activity-dependent synaptic plasticity (13,14).…”

Section: Methodsmentioning

confidence: 99%

“…ADAM10 is an integral component of postsynaptic densities (PSDs) of excitatory synapses (12)(13)(14) and binds to synapse-associated protein-97 (SAP97), a member of the MAGUK family of protein scaffolds that governs the trafficking and synaptic anchoring of AMPA-and NMDA-type glutamate receptors. The interaction involves the SH3 domain of SAP97 and an atypical proline-rich domain within the C-terminal region of ADAM10, and favours the forward trafficking of ADAM10 and its localization in synaptic membranes and, thereby, its APP-cleaving activity (12).…”

Section: Introductionmentioning

confidence: 99%

Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer’s disease

Marcello¹,

Saraceno²,

Musardo³

et al. 2013

J. Clin. Invest.

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100

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A disintegrin and metalloproteinase 10 (ADAM10), a disintegrin and metalloproteinase that resides in the postsynaptic densities (PSDs) of excitatory synapses, has previously been shown to limit β-amyloid peptide (Aβ) formation in Alzheimer's disease (AD). ADAM10 also plays a critical role in regulating functional membrane proteins at the synapse. Using human hippocampal homogenates, we found that ADAM10 removal from the plasma membrane was mediated by clathrin-dependent endocytosis. Additionally, we identified the clathrin adaptor AP2 as an interacting partner of a previously uncharacterized atypical binding motif in the ADAM10 C-terminal domain. This domain was required for ADAM10 endocytosis and modulation of its plasma membrane levels. We found that the ADAM10/AP2 association was increased in the hippocampi of AD patients compared with healthy controls. Long-term potentiation (LTP) in hippocampal neuronal cultures induced ADAM10 endocytosis through AP2 association and decreased surface ADAM10 levels and activity. Conversely, long-term depression (LTD) promoted ADAM10 synaptic membrane insertion and stimulated its activity. ADAM10 interaction with the synapse-associated protein-97 (SAP97) was necessary for LTD-induced ADAM10 trafficking and required for LTD maintenance and LTD-induced changes in spine morphogenesis. These data identify and characterize a mechanism controlling ADAM10 localization and activity at excitatory synapses that is relevant to AD pathogenesis.

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“…Analysis of dendritic spine morphology was performed with ImageJ software; for each dendritic spine length, the head and neck width were measured, which was used to classify dendritic spines into three categories (thin, stubby and mushroom) (Harris et al, 1992). In particular, the length and the ratio between the width of head and the width of neck (Wh/Wn) were used as parameters for the classification as follows: protrusions having a length of more than 3 µm were considered as filopodia, the others as spines; spines with a Wh/Wn ratio bigger than 1.7 were considered mushrooms; spines with a Wh/Wn ratio smaller than 1.7 were divided in stubby, if shorter than 1 µm, and thin if longer than 1 µm (Gardoni et al, 2012). An operator who was 'blind' to the experimental conditions performed both image acquisition and quantification.…”

Section: Dendritic Spine Labeling and Morphological Classificationmentioning

confidence: 99%

Short-term withdrawal from developmental exposure to cocaine activates the glucocorticoid receptor and alters spine dynamics

Caffino

Giannotti

Malpighi

et al. 2015

European Neuropsychopharmacology

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Although glucocorticoid receptors (GRs) contribute to the action of cocaine, their role following developmental exposure to the psychostimulant is still unknown. To address this issue, we exposed adolescent male rats to cocaine (20mg/kg/day) from post-natal day (PND) 28 to PND 42 and sacrificed them at PND 45 or 90. We studied the medial prefrontal cortex (mPFC), a brain region that is still developing during adolescence. In PND 45 rats we found enhanced GR transcription and translation as well as increased trafficking toward the nucleus of the receptor, with no alteration in plasma corticosterone levels. We also showed reduced expression of the GR co-chaperone FKBP51, that normally keeps the receptor in the cytoplasm, and increased expression of Src1, which cooperates in the activation of GR transcriptional activity, revealing that short withdrawal alter the finely tuned mechanisms regulating GR action. Since activation of GRs regulate dendritic spine morphology, we next investigated spine dynamics in cocaine-withdrawn rats. We found that PSD95, cofilin and F-actin, molecules regulating spine actin network, are reduced in the mPFC of PND 45 rats suggesting reduced spine density, confirmed by confocal imaging. Further, formation of filopodia, i.e. the inactive spines, is enhanced suggesting the formation of non-functional spines.Of note, no changes were found in molecules related to GR machinery or spine dynamics following long-term abstinence, i.e. in adult rats (PND 90). These findings demonstrate that short withdrawal promotes plastic changes in the developing brain via the dysregulation of the GR system and alterations in the spine network.

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

Cited by 33 publications

References 25 publications

Regulation of AMPA receptor phosphorylation by the neuropeptide PACAP38

Regulation of AMPA receptor phosphorylation by the neuropeptide PACAP38

Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer’s disease

Short-term withdrawal from developmental exposure to cocaine activates the glucocorticoid receptor and alters spine dynamics

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