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Differential regulation of STP, LTP and LTD by structurally diverse NMDA receptor subunit-specific positive allosteric modulators

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dc.contributor.authorFrance, G.en
dc.contributor.authorVolianskis, R.en
dc.contributor.authorIngram, R.en
dc.contributor.authorBannister, N.en
dc.contributor.authorRotharmel, R.en
dc.contributor.authorIrvine, M. W.en
dc.contributor.authorFang, G.en
dc.contributor.authorBurnell, E. S.en
dc.contributor.authorSapkota, K.en
dc.contributor.authorCosta, Blaise M.en
dc.contributor.authorChopra, D. A.en
dc.contributor.authorDravid, S. M.en
dc.contributor.authorMichael-Titus, A. T.en
dc.contributor.authorMonaghan, D. T.en
dc.contributor.authorGeorgiou, J.en
dc.contributor.authorBortolotto, Z. A.en
dc.contributor.authorJane, D. E.en
dc.contributor.authorCollingridge, G. L.en
dc.contributor.authorVolianskis, A.en
dc.date.accessioned2022-09-19T17:26:21Zen
dc.date.available2022-09-19T17:26:21Zen
dc.date.issued2022-01-01en
dc.description.abstractDifferent types of memory are thought to rely on different types of synaptic plasticity, many of which depend on the activation of the N-Methyl-D Aspartate (NMDA) subtype of glutamate receptors. Accordingly, there is considerable interest in the possibility of using positive allosteric modulators (PAMs) of NMDA receptors (NMDARs) as cognitive enhancers. Here we firstly review the evidence that NMDA receptor-dependent forms of synaptic plasticity: short-term potentiation (STP), long-term potentiation (LTP) and long-term depression (LTD) can be pharmacologically differentiated by using NMDAR ligands. These observations suggest that PAMs of NMDAR function, depending on their subtype selectivity, might differentially regulate STP, LTP and LTD. To test this hypothesis, we secondly performed experiments in rodent hippocampal slices with UBP714 (a GluN2A/2B preferring PAM), CIQ (a GluN2C/D selective PAM) and UBP709 (a pan-PAM that potentiates all GluN2 subunits). We report here, for the first time, that: (i) UBP714 potentiates sub-maximal LTP and reduces LTD; (ii) CIQ potentiates STP without affecting LTP; (iii) UBP709 enhances LTD and decreases LTP. We conclude that PAMs can differentially regulate distinct forms of NMDAR-dependent synaptic plasticity due to their subtype selectivity.en
dc.description.notesSupported by (1) The Blizard Institute QMUL (AV), (2) CIHR (Canadian Institutes of Health Research) Foundation Grant #154276 (GLC.), (3) `The Neuroscience Catalyst' research program of the Centre for Collaborative Drug Research (CCDR) at the University of Toronto (GLC and JG), (4) NIH R01MH060252 (MDT and JDE), (5) MRC G0601812, MR/K023098/1 (GLC) and (6) BBSRC BB/L001977/1 (JDE), (7) GLC is supported by the Krembil Family Chair in Alzheimer's Research.en
dc.description.sponsorshipBlizard Institute QMUL; CIHR (Canadian Institutes of Health Research) Foundation Grant [154276]; Neuroscience Catalyst' research program of the Centre for Collaborative Drug Research (CCDR) at the University of Toronto; NIH [R01MH060252]; MRC [G0601812, MR/K023098/1]; BBSRC [BB/L001977/1]; Krembil Family Chair in Alzheimer's Researchen
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1016/j.neuropharm.2021.108840en
dc.identifier.eissn1873-7064en
dc.identifier.issn0028-3908en
dc.identifier.other108840en
dc.identifier.pmid34678377en
dc.identifier.urihttp://hdl.handle.net/10919/111856en
dc.identifier.volume202en
dc.language.isoenen
dc.publisherPergamon-Elsevieren
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectNMDA receptorsen
dc.subjectShort-term potentiationen
dc.subjectSTPen
dc.subjectLong-term potentiationen
dc.subjectLTPen
dc.subjectLong-term depressionen
dc.subjectLTDen
dc.subjectPositive allosteric modulator (PAM)en
dc.subjectSynaptic plasticityen
dc.subjectMemoryen
dc.titleDifferential regulation of STP, LTP and LTD by structurally diverse NMDA receptor subunit-specific positive allosteric modulatorsen
dc.title.serialNeuropharmacologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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