A PARP1-ERK2 synergism is required for the induction of LTP

Visochek, Leonid; Grigoryan, G. A.; Kalal, Adi; Milshtein-Parush, Hila; Gazit, Neta; Slutsky, Inna; Yeheskel, Adva; Shainberg, Asher; Castiel, Asher; Seger, Rony; Langelier, Marie-France; Dantzer, Françoise; Pascal, John M.; Segal, Menahem; Cohen-Armon, Malka

doi:10.1038/srep24950

Cited by 17 publications

(49 citation statements)

References 63 publications

(160 reference statements)

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“…Recent evidence shows inhibition of PARP1 causes loss of LTP induction in rodents [145,146]. Disruption of PARP1-ERK2 protein-protein interactions in the nucleus were responsible for this loss [145,146]. Our bioinformatic analyses suggests that synaptic protein-protein interactions with CaMKIIα, CaMKIIβ, PRKCG, or NSF may be disrupted by PARP1…”

Section: Discussionmentioning

confidence: 80%

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Region-Specific PSD-95 Interactomes Contribute to Functional Diversity of Excitatory Synapses in Human Brain

Funk

Labilloy

Reigle

et al. 2020

Preprint

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Running title -PSD-95 protein-protein interactions in human brainThe overarching goal of this exploratory study is to link subcellular microdomain specific protein-protein interactomes with big data analytics. We isolated postsynaptic density-95 (PSD-95) complexes from four human brain regions and compared their protein interactomes using multiple bioinformatics techniques. We demonstrate that human brain regions have unique postsynaptic protein signatures that may be used to interrogate perturbagen databases. Assessment of our hippocampal signature using the iLINCS database yielded several compounds with recently characterized "off target" effects on protein-protein interactions in the posynaptic density compartment. Acknowledgments:We would like to thank all those that have supported this research: the L.I.F.E. Foundation, UCNI pilot award, Lindsay Brinkmeyer Schizophrenia Research Fund, Center for Clinical and Translational Science Training (CCTST), and NIH grant MH107916. The MS data was acquired in the University of Cincinnati Proteomics Laboratory on a mass spectrometer funded in part through the NIH S10 shared instrumentation grant RR027015.Altering the expression of PSD-95 protein significantly changes synaptic structure and function, including molecular correlates of learning and memory, long-term potentiation (LTP) and long-term depression (LTD). For example, PSD-95 overexpression increases the amplitude of excitatory postsynaptic currents (EPSCs), to the extent that additional stimulus is unable to further strengthen LTP [13][14][15][16][17]. In contrast, PSD-95 knockdown disrupts postsynaptic density structure and suppresses EPSCs, consistent with a role for PSD-95 in synaptic fidelity [18][19][20]. Further highlighting the importance of PSD-95 in the synapse, knockout of PSD-95 in mice and genomic variants within postsynaptic density hub proteins are particularly implicated in neuropsychiatric disorders such as schizophrenia and autism [21,22].To investigate excitatory postsynaptic protein hubs, we targeted PSD-95 due to its high level of localization to the postsynaptic density (~95%), its well-characterized role as a hub protein, and the large number of constituents in its protein interactome (~1000) [23][24][25]. We designed a series of experiments to examine brain region-specific excitatory postsynaptic proteomes to answer the following questions. 1) Do postsynaptic protein-protein interactions differ by brain region? 2) Can we accurately detect and separate samples based on these differences? and 3) Can region-specific protein interactomes inform functional differences? For these experiments we used four human brain regions (anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), hippocampus (HPC), and superior temporal gyrus (STG)) from 3 well-matched control male subjects from the Alabama Brain Collection. A total of 289 proteins were identified as part of a PSD-95 protein interactome that were present across all four brain regions.We hypothesize that there is region-specific ...

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Section: Discussionmentioning

confidence: 80%

“…For example, we found a strongly discordant (to the HPC) signature for PARP1 inhibitor analog, AG14361. Recent evidence shows inhibition of PARP1 causes loss of LTP induction in rodents [145,146]. Disruption of PARP1-ERK2 protein-protein interactions in the nucleus were responsible for this loss [145,146].…”

Section: Discussionmentioning

confidence: 99%

Region-Specific PSD-95 Interactomes Contribute to Functional Diversity of Excitatory Synapses in Human Brain

Funk

Labilloy

Reigle

et al. 2020

Preprint

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“…PARP inhibitors have been shown to interfere with the formation of long-term potentiation (LTP) and can disrupt long-term memory formation in Aplysia bathed in inhibitors ( Cohen-Armon et al, 2004 ) and in mice when inhibitors are infused into the cerebral ventricles ( Goldberg et al, 2009 ). PARP knockout mice also demonstrate defects in LTP formation ( Visochek et al, 2016 ). It is difficult to compare the levels of PARP inhibition in these studies with those achieved by doses of PARP inhibitors administered subcutaneously or intraperitoneally to rats in the present study.…”

Section: Discussionmentioning

confidence: 99%

Antidepressant-Like Actions of Inhibitors of Poly(ADP-Ribose) Polymerase in Rodent Models

Ordway

Szebeni

Hernandez

et al. 2017

International Journal of Neuropsychopharmacology

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BackgroundMany patients suffering from depressive disorders are refractory to treatment with currently available antidepressant medications, while many more exhibit only a partial response. These factors drive research to discover new pharmacological approaches to treat depression. Numerous studies demonstrate evidence of inflammation and elevated oxidative stress in major depression. Recently, major depression has been shown to be associated with elevated levels of DNA oxidation in brain cells, accompanied by increased gene expression of the nuclear base excision repair enzyme, poly(ADP-ribose) polymerase-1. Given these findings and evidence that drugs that inhibit poly(ADP-ribose) polymerase-1 activity have antiinflammatory and neuroprotective properties, the present study was undertaken to examine the potential antidepressant properties of poly(ADP-ribose) polymerase inhibitors.MethodsTwo rodent models, the Porsolt swim test and repeated exposure to psychological stressors, were used to test the poly(ADP-ribose) polymerase inhibitor, 3-aminobenzamide, for potential antidepressant activity. Another poly(ADP-ribose) polymerase inhibitor, 5-aminoisoquinolinone, was also tested.ResultsPoly(ADP-ribose) polymerase inhibitors produced antidepressant-like effects in the Porsolt swim test, decreasing immobility time, and increasing latency to immobility, similar to the effects of fluoxetine. In addition, 3-aminobenzamide treatment increased sucrose preference and social interaction times relative to vehicle-treated control rats following repeated exposure to combined social defeat and unpredictable stress, mediating effects similar to fluoxetine treatment.ConclusionsThe poly(ADP-ribose) polymerase inhibitors 3-aminobenzamide and 5-aminoisoquinolinone exhibit antidepressant-like activity in 2 rodent stress models and uncover poly(ADP-ribose) polymerase as a unique molecular target for the potential development of a novel class of antidepressants.

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“…41 In the mouse hippocampus, an increase in nuclear Poly(ADP-ribose) polymerase-1 and Poly(ADP) ribose molecules during the Foskolininduced LTP is regulated by the activation of cAMPdependent protein kinase (PKA) and ERK. [42][43][44]…”

Section: Erks and Learning-related Hippocampal Ltpmentioning

confidence: 99%

Presynaptic long-term potentiation requires extracellular signal-regulated kinases in the anterior cingulate cortex

et al. 2020

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Extracellular signal-regulated kinases are widely expressed protein kinases in neurons, which serve as important intracellular signaling molecules for central plasticity such as long-term potentiation. Recent studies demonstrate that there are two major forms of long-term potentiation in cortical areas related to pain: postsynaptic long-term potentiation and presynaptic long-term potentiation. In particular, presynaptic long-term potentiation in the anterior cingulate cortex has been shown to contribute to chronic pain-related anxiety. In this review, we briefly summarized the components and roles of extracellular signal-regulated kinases in neuronal signaling, especially in the presynaptic long-term potentiation of anterior cingulate cortex, and discuss the possible molecular mechanisms and functional implications in pain-related emotional disorders.

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A PARP1-ERK2 synergism is required for the induction of LTP

Cited by 17 publications

References 63 publications

Region-Specific PSD-95 Interactomes Contribute to Functional Diversity of Excitatory Synapses in Human Brain

Region-Specific PSD-95 Interactomes Contribute to Functional Diversity of Excitatory Synapses in Human Brain

Antidepressant-Like Actions of Inhibitors of Poly(ADP-Ribose) Polymerase in Rodent Models

Presynaptic long-term potentiation requires extracellular signal-regulated kinases in the anterior cingulate cortex

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