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

France, G., Volianskis, R., Ingram, R., Bannister, N., Rothärmel, R., Irvine, M.W., Fang, G., Burnell, E.S., Sapkota, K., Costa, B.M., Chopra, D.A., Dravid, S.M., Michael-Titus, A.T., Monaghan, D.T., Georgiou, J, Bortolotto, Z.A., Jane, D.E., Collingridge, G.L. and Volianskis, A. 2022. Differential regulation of STP, LTP and LTD by structurally diverse NMDA receptor subunit-specific positive allosteric modulators. Neuropharmacology 202 , 108840. 10.1016/j.neuropharm.2021.108840

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Abstract

Different 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Elsevier
ISSN: 0028-3908
Date of First Compliant Deposit: 18 January 2022
Date of Acceptance: 13 October 2021
Last Modified: 03 May 2023 23:45
URI: https://orca.cardiff.ac.uk/id/eprint/146751

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