The Contribution of AMPA and NMDA Receptors to Persistent Firing in the Dorsolateral Prefrontal Cortex in Working Memory

Bram van Vugt, Timo van Kerkoerle, Devavrat Vartak, Pieter R. Roelfsema

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Many tasks demand that information is kept online for a few seconds before it is used to guide behavior. The information is kept in working memory as the persistent firing of neurons encoding the memorized information. The neural mechanisms responsible for persistent activity are not yet well understood. Theories attribute an important role to ionotropic glutamate receptors, and it has been suggested that NMDARs are particularly important for persistent firing because they exhibit long time constants. Ionotropic AMPARs have shorter time constants and have been suggested to play a smaller role in working memory. Here we compared the contribution of AMPARs and NMDARs to persistent firing in the dlPFC of male macaque monkeys performing a delayed saccade to a memorized spatial location. We used iontophoresis to eject small amounts of glutamate receptor antagonists, aiming to perturb, but not abolish, neuronal activity. We found that both AMPARs and NMDARs contributed to persistent activity. Blockers of the NMDARs decreased persistent firing associated with the memory of the neuron's preferred spatial location but had comparatively little effect on the representation of the antipreferred location. They therefore decreased the information conveyed by persistent firing about the memorized location. In contrast, AMPAR blockers decreased activity elicited by the memory of both the preferred and antipreferred location, with a smaller effect on the information conveyed by persistent activity. Our results provide new insights into the contribution of AMPARs and NMDARs to persistent activity during working memory tasks.SIGNIFICANCE STATEMENT Working memory enables us to hold on to information that is no longer available to the senses. It relies on the persistent activity of neurons that code for the memorized information, but the detailed mechanisms are not yet well understood. Here we investigated the role of NMDARs and AMPARs in working memory using iontophoresis of antagonists in the PFC of monkeys remembering the location of a visual stimulus for an eye movement response. AMPARs and NMDARs both contributed to persistent activity. NMDAR blockers mostly decreased persistent firing associated with the memory of the neuron's preferred spatial location, whereas AMPAR blockers caused a more general suppression. These results provide new insight into the contribution of AMPARs and NMDARs to working memory.

Original languageEnglish
Pages (from-to)2458-2470
Number of pages13
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience
Volume40
Issue number12
DOIs
Publication statusPublished - 18 Mar 2020

Funding

P.R.R. was supported by NWO (ALW Grant 823-02-010), European Union (Marie-Curie Action PITN-GA-2011-290011; Human Brain Project, Grant Agreements 7202070 and 785907, and ERC Grant Agreement 339490 “Cortic_al_gorithms”),andFriendsFoundationofTheNetherlandsInstituteforNeuroscience.WethankProf.Alexander Thiele and Jose Herrero for help in setting up the iontophoresis method; and Kor Brandsma and Anneke Ditewig for biotechnical assistance. P.R.R. was supported by NWO (ALW Grant 823-02-010), European Union (Marie-Curie Action PITN-GA-2011-290011; Human Brain Project, Grant Agreements 7202070 and 785907, and ERC Grant Agreement 339490 ?Cortic_al_gorithms?), and Friends Foundation of The Netherlands Institute for Neuroscience. We thank Prof. Alexander Thiele and Jose Herrero for help in setting up the iontophoresis method; and Kor Brandsma and Anneke Ditewig for biotechnical assistance.

FundersFunder number
Friends Foundation of the Netherlands Institute for Neuroscience
Horizon 2020 Framework Programme339490, 290011
European Commission785907, 7202070, PITN-GA-2011-290011
European Research Council
Nederlandse Organisatie voor Wetenschappelijk Onderzoek823-02-010

    Keywords

    • AMPAR
    • macaque monkey
    • NMDAR
    • PFC
    • working memory

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