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Molecular Pharmacology

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Research ArticleArticle

GluN2D-Containing N-methyl-d-Aspartate Receptors Mediate Synaptic Transmission in Hippocampal Interneurons and Regulate Interneuron Activity

Riley E. Perszyk, John O. DiRaddo, Katie L. Strong, Chian-Ming Low, Kevin K. Ogden, Alpa Khatri, Geoffrey A. Vargish, Kenneth A. Pelkey, Ludovic Tricoire, Dennis C. Liotta, Yoland Smith, Chris J. McBain and Stephen F. Traynelis
Molecular Pharmacology December 2016, 90 (6) 689-702; DOI: https://doi.org/10.1124/mol.116.105130
Riley E. Perszyk
Departments of Pharmacology (R.E.P., J.O.D., K.K.O., A.K., S.F.T.), Chemistry (J.O.D., K.L.S., D.C.L.), Neurology (Y.S.), Yerkes National Primate Research Center (Y.S.), and Morris K. Udall Center of Excellence for Parkinson’s Disease Research (Y.S.), Emory University, Atlanta, Georgia; Departments of Pharmacology and Anaesthesiology (C.-M.L.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (G.A.V., K.A.P., L.T., C.J.M.), National Institutes of Health, Bethesda, Maryland
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John O. DiRaddo
Departments of Pharmacology (R.E.P., J.O.D., K.K.O., A.K., S.F.T.), Chemistry (J.O.D., K.L.S., D.C.L.), Neurology (Y.S.), Yerkes National Primate Research Center (Y.S.), and Morris K. Udall Center of Excellence for Parkinson’s Disease Research (Y.S.), Emory University, Atlanta, Georgia; Departments of Pharmacology and Anaesthesiology (C.-M.L.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (G.A.V., K.A.P., L.T., C.J.M.), National Institutes of Health, Bethesda, Maryland
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Katie L. Strong
Departments of Pharmacology (R.E.P., J.O.D., K.K.O., A.K., S.F.T.), Chemistry (J.O.D., K.L.S., D.C.L.), Neurology (Y.S.), Yerkes National Primate Research Center (Y.S.), and Morris K. Udall Center of Excellence for Parkinson’s Disease Research (Y.S.), Emory University, Atlanta, Georgia; Departments of Pharmacology and Anaesthesiology (C.-M.L.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (G.A.V., K.A.P., L.T., C.J.M.), National Institutes of Health, Bethesda, Maryland
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Chian-Ming Low
Departments of Pharmacology (R.E.P., J.O.D., K.K.O., A.K., S.F.T.), Chemistry (J.O.D., K.L.S., D.C.L.), Neurology (Y.S.), Yerkes National Primate Research Center (Y.S.), and Morris K. Udall Center of Excellence for Parkinson’s Disease Research (Y.S.), Emory University, Atlanta, Georgia; Departments of Pharmacology and Anaesthesiology (C.-M.L.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (G.A.V., K.A.P., L.T., C.J.M.), National Institutes of Health, Bethesda, Maryland
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Kevin K. Ogden
Departments of Pharmacology (R.E.P., J.O.D., K.K.O., A.K., S.F.T.), Chemistry (J.O.D., K.L.S., D.C.L.), Neurology (Y.S.), Yerkes National Primate Research Center (Y.S.), and Morris K. Udall Center of Excellence for Parkinson’s Disease Research (Y.S.), Emory University, Atlanta, Georgia; Departments of Pharmacology and Anaesthesiology (C.-M.L.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (G.A.V., K.A.P., L.T., C.J.M.), National Institutes of Health, Bethesda, Maryland
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Alpa Khatri
Departments of Pharmacology (R.E.P., J.O.D., K.K.O., A.K., S.F.T.), Chemistry (J.O.D., K.L.S., D.C.L.), Neurology (Y.S.), Yerkes National Primate Research Center (Y.S.), and Morris K. Udall Center of Excellence for Parkinson’s Disease Research (Y.S.), Emory University, Atlanta, Georgia; Departments of Pharmacology and Anaesthesiology (C.-M.L.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (G.A.V., K.A.P., L.T., C.J.M.), National Institutes of Health, Bethesda, Maryland
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Geoffrey A. Vargish
Departments of Pharmacology (R.E.P., J.O.D., K.K.O., A.K., S.F.T.), Chemistry (J.O.D., K.L.S., D.C.L.), Neurology (Y.S.), Yerkes National Primate Research Center (Y.S.), and Morris K. Udall Center of Excellence for Parkinson’s Disease Research (Y.S.), Emory University, Atlanta, Georgia; Departments of Pharmacology and Anaesthesiology (C.-M.L.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (G.A.V., K.A.P., L.T., C.J.M.), National Institutes of Health, Bethesda, Maryland
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Kenneth A. Pelkey
Departments of Pharmacology (R.E.P., J.O.D., K.K.O., A.K., S.F.T.), Chemistry (J.O.D., K.L.S., D.C.L.), Neurology (Y.S.), Yerkes National Primate Research Center (Y.S.), and Morris K. Udall Center of Excellence for Parkinson’s Disease Research (Y.S.), Emory University, Atlanta, Georgia; Departments of Pharmacology and Anaesthesiology (C.-M.L.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (G.A.V., K.A.P., L.T., C.J.M.), National Institutes of Health, Bethesda, Maryland
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Ludovic Tricoire
Departments of Pharmacology (R.E.P., J.O.D., K.K.O., A.K., S.F.T.), Chemistry (J.O.D., K.L.S., D.C.L.), Neurology (Y.S.), Yerkes National Primate Research Center (Y.S.), and Morris K. Udall Center of Excellence for Parkinson’s Disease Research (Y.S.), Emory University, Atlanta, Georgia; Departments of Pharmacology and Anaesthesiology (C.-M.L.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (G.A.V., K.A.P., L.T., C.J.M.), National Institutes of Health, Bethesda, Maryland
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Dennis C. Liotta
Departments of Pharmacology (R.E.P., J.O.D., K.K.O., A.K., S.F.T.), Chemistry (J.O.D., K.L.S., D.C.L.), Neurology (Y.S.), Yerkes National Primate Research Center (Y.S.), and Morris K. Udall Center of Excellence for Parkinson’s Disease Research (Y.S.), Emory University, Atlanta, Georgia; Departments of Pharmacology and Anaesthesiology (C.-M.L.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (G.A.V., K.A.P., L.T., C.J.M.), National Institutes of Health, Bethesda, Maryland
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Yoland Smith
Departments of Pharmacology (R.E.P., J.O.D., K.K.O., A.K., S.F.T.), Chemistry (J.O.D., K.L.S., D.C.L.), Neurology (Y.S.), Yerkes National Primate Research Center (Y.S.), and Morris K. Udall Center of Excellence for Parkinson’s Disease Research (Y.S.), Emory University, Atlanta, Georgia; Departments of Pharmacology and Anaesthesiology (C.-M.L.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (G.A.V., K.A.P., L.T., C.J.M.), National Institutes of Health, Bethesda, Maryland
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Chris J. McBain
Departments of Pharmacology (R.E.P., J.O.D., K.K.O., A.K., S.F.T.), Chemistry (J.O.D., K.L.S., D.C.L.), Neurology (Y.S.), Yerkes National Primate Research Center (Y.S.), and Morris K. Udall Center of Excellence for Parkinson’s Disease Research (Y.S.), Emory University, Atlanta, Georgia; Departments of Pharmacology and Anaesthesiology (C.-M.L.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (G.A.V., K.A.P., L.T., C.J.M.), National Institutes of Health, Bethesda, Maryland
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Stephen F. Traynelis
Departments of Pharmacology (R.E.P., J.O.D., K.K.O., A.K., S.F.T.), Chemistry (J.O.D., K.L.S., D.C.L.), Neurology (Y.S.), Yerkes National Primate Research Center (Y.S.), and Morris K. Udall Center of Excellence for Parkinson’s Disease Research (Y.S.), Emory University, Atlanta, Georgia; Departments of Pharmacology and Anaesthesiology (C.-M.L.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (G.A.V., K.A.P., L.T., C.J.M.), National Institutes of Health, Bethesda, Maryland
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Abstract

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamatergic receptors that have been implicated in learning, development, and neuropathological conditions. They are typically composed of GluN1 and GluN2A-D subunits. Whereas a great deal is known about the role of GluN2A- and GluN2B-containing NMDARs, much less is known about GluN2D-containing NMDARs. Here we explore the subunit composition of synaptic NMDARs on hippocampal interneurons. GluN2D mRNA was detected by single-cell PCR and in situ hybridization in diverse interneuron subtypes in the CA1 region of the hippocampus. The GluN2D subunit was detectable by immunoblotting and immunohistochemistry in all subfields of the hippocampus in young and adult mice. In whole-cell patch-clamp recordings from acute hippocampal slices, (+)-CIQ, the active enantiomer of the positive allosteric modulator CIQ, significantly enhanced the amplitude of the NMDAR component of miniature excitatory postsynaptic currents (mEPSCs) in CA1 interneurons but not in pyramidal cells. (+)-CIQ had no effect in slices from Grin2d−/− mice, suggesting that GluN2D-containing NMDARs participate in excitatory synaptic transmission onto hippocampal interneurons. The time course of the NMDAR component of the mEPSC was unaffected by (+)-CIQ potentiation and was not accelerated in slices from Grin2d−/− mice compared with wild-type, suggesting that GluN2D does not detectably slow the NMDAR EPSC time course at this age. (+)-CIQ increased the activity of CA1 interneurons as detected by the rate and net charge transfer of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from CA1 pyramidal cells. These data provide evidence that interneurons contain synaptic NMDARs possessing a GluN2D subunit, which can influence interneuron function and signal processing.

Footnotes

    • Received May 13, 2016.
    • Accepted September 12, 2016.
  • This work was supported by the National Institutes of Health (NIH) National Institute of Neurologic Disorders and Stroke [Grants RO1-NS036654, RO1-NS065371], NIH National Institute of General Medical Sciences [Grant T32-GM008602], and NIH Office of Research Infrastructure Programs [Grant P51OD011132]. This research was supported [in part] by the Intramural Research Program of the NIH National Institute of Child Health and Human Development.

  • dx.doi.org/10.1124.mol.116.105130.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 90 (6)
Molecular Pharmacology
Vol. 90, Issue 6
1 Dec 2016
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Research ArticleArticle

Synaptic GluN2D NMDA Receptors in Interneurons

Riley E. Perszyk, John O. DiRaddo, Katie L. Strong, Chian-Ming Low, Kevin K. Ogden, Alpa Khatri, Geoffrey A. Vargish, Kenneth A. Pelkey, Ludovic Tricoire, Dennis C. Liotta, Yoland Smith, Chris J. McBain and Stephen F. Traynelis
Molecular Pharmacology December 1, 2016, 90 (6) 689-702; DOI: https://doi.org/10.1124/mol.116.105130

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Research ArticleArticle

Synaptic GluN2D NMDA Receptors in Interneurons

Riley E. Perszyk, John O. DiRaddo, Katie L. Strong, Chian-Ming Low, Kevin K. Ogden, Alpa Khatri, Geoffrey A. Vargish, Kenneth A. Pelkey, Ludovic Tricoire, Dennis C. Liotta, Yoland Smith, Chris J. McBain and Stephen F. Traynelis
Molecular Pharmacology December 1, 2016, 90 (6) 689-702; DOI: https://doi.org/10.1124/mol.116.105130
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