GluN2D-Containing N-methyl-d-Aspartate Receptors Mediate Synaptic Transmission in Hippocampal Interneurons and Regulate Interneuron Activity.
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.
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.
Riley E
RE
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.
John O
JO
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.
Katie L
KL
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.
Chian-Ming
CM
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.
Kevin K
KK
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.
Alpa
A
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.
Geoffrey A
GA
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.
Kenneth A
KA
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.
Ludovic
L
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.
Dennis C
DC
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.
Yoland
Y
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.
Chris J
CJ
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 strayne@emory.edu.
Stephen F
SF
Traynelis
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology*; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors; D014982:Xenopus laevis
C551080:(6,7-dimethoxy-4-methylisoquinolinyl)-(4'-methoxyphenyl)methanone; D007546:Isoquinolines; C464436:NR2D NMDA receptor; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate