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Presynaptic Effects of N-Methyl-D-Aspartate Receptors Enhance Parvalbumin Cell–Mediated Inhibition of Pyramidal Cells in Mouse Prefrontal Cortex

  • Diego E. Pafundo
    Affiliations
    Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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  • Takeaki Miyamae
    Affiliations
    Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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  • David A. Lewis
    Affiliations
    Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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  • Guillermo Gonzalez-Burgos
    Correspondence
    Address correspondence to Guillermo Gonzalez-Burgos, Ph.D., Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, W1647 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261.
    Affiliations
    Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Published:February 03, 2018DOI:https://doi.org/10.1016/j.biopsych.2018.01.018

      Abstract

      Background

      Testing hypotheses regarding the role of N-methyl-D-aspartate receptor (NMDAR) hypofunction in schizophrenia requires understanding the mechanisms of NMDAR regulation of prefrontal cortex (PFC) circuit function. NMDAR antagonists are thought to produce pyramidal cell (PC) disinhibition. However, inhibitory parvalbumin-positive basket cells (PVBCs) have modest NMDAR-mediated excitatory drive and thus are unlikely to participate in NMDAR antagonist–mediated disinhibition. Interestingly, recent studies demonstrated that presynaptic NMDARs enhance transmitter release at central synapses. Thus, if presynaptic NMDARs enhance gamma-aminobutyric acid release at PVBC-to-PC synapses, they could participate in NMDAR-dependent PC disinhibition. Here, we examined whether presynaptic NMDAR effects could modulate gamma-aminobutyric acid release at PVBC-to-PC synapses in mouse PFC.

      Methods

      Using whole-cell recordings from synaptically connected pairs in mouse PFC, we determined whether NMDA or NMDAR antagonist application affects PVBC-to-PC inhibition in a manner consistent with a presynaptic mechanism.

      Results

      NMDAR activation enhanced by ∼40% the synaptic current at PVBC-to-PC pairs. This effect was consistent with a presynaptic mechanism given that it was 1) observed with postsynaptic NMDARs blocked by intracellular MK801, 2) associated with a lower rate of transmission failures and a higher transmitter release probability, and 3) blocked by intracellular MK801 in the PVBC. NMDAR antagonist application did not affect the synaptic currents in PVBC-to-PC pairs, but it reduced the inhibitory currents elicited in PCs with simultaneous glutamate release by extracellular stimulation.

      Conclusions

      We demonstrate that NMDAR activation enhances PVBC-to-PC inhibition in a manner consistent with presynaptic mechanisms, and we suggest that the functional impact of this presynaptic effect depends on the activity state of the PFC network.

      Keywords

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      References

        • Javitt D.C.
        • Zukin S.R.
        Recent advances in the phencyclidine model of schizophrenia.
        Am J Psychiatry. 1991; 148: 1301-1308
        • Krystal J.H.
        • Karper L.P.
        • Seibyl J.P.
        • Freeman G.K.
        • Delaney R.
        • Bremner J.D.
        • et al.
        Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses.
        Arch Gen Psychiatry. 1994; 51: 199-214
        • Lahti A.C.
        • Koffel B.
        • LaPorte D.
        • Tamminga C.A.
        Subanesthetic doses of ketamine stimulate psychosis in schizophrenia.
        Neuropsychopharmacology. 1995; 13: 9-19
        • Coyle J.T.
        The glutamatergic dysfunction hypothesis for schizophrenia.
        Harv Rev Psychiatry. 1996; 3: 241-253
        • Homayoun H.
        • Moghaddam B.
        NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons.
        J Neurosci. 2007; 27: 11496-11500
        • Lewis D.A.
        • Moghaddam B.
        Cognitive dysfunction in schizophrenia: Convergence of gamma-aminobutyric acid and glutamate alterations.
        Arch Neurol. 2006; 63: 1372-1376
        • Hu H.
        • Gan J.
        • Jonas P.
        Fast-spiking, parvalbumin+ GABAergic interneurons: From cellular design to microcircuit function.
        Science. 2014; 345: 1255263
        • Gonzalez-Burgos G.
        • Cho R.Y.
        • Lewis D.A.
        Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia.
        Biol Psychiatry. 2015; 77: 1031-1040
        • Enwright J.F.
        • Sanapala S.
        • Foglio A.
        • Berry R.
        • Fish K.N.
        • Lewis D.A.
        Reduced labeling of parvalbumin neurons and perineuronal nets in the dorsolateral prefrontal cortex of subjects with schizophrenia.
        Neuropsychopharmacology. 2016; 41: 2206-2214
        • Chung D.W.
        • Fish K.N.
        • Lewis D.A.
        Pathological basis for deficient excitatory drive to cortical parvalbumin interneurons in schizophrenia.
        Am J Psychiatry. 2016; 173: 1131-1139
        • Angulo M.C.
        • Rossier J.
        • Audinat E.
        Postsynaptic glutamate receptors and integrative properties of fast-spiking interneurons in the rat neocortex.
        J Neurophysiol. 1999; 82: 1295-1302
        • Lu J.T.
        • Li C.Y.
        • Zhao J.P.
        • Poo M.M.
        • Zhang X.H.
        Spike-timing-dependent plasticity of neocortical excitatory synapses on inhibitory interneurons depends on target cell type.
        J Neurosci. 2007; 27: 9711-9720
        • Hull C.
        • Isaacson J.S.
        • Scanziani M.
        Postsynaptic mechanisms govern the differential excitation of cortical neurons by thalamic inputs.
        J Neurosci. 2009; 29: 9127-9136
        • Wang H.X.
        • Gao W.J.
        Cell type-specific development of NMDA receptors in the interneurons of rat prefrontal cortex.
        Neuropsychopharmacology. 2009; 34: 2028-2040
        • Rotaru D.C.
        • Yoshino H.
        • Lewis D.A.
        • Ermentrout G.B.
        • Gonzalez-Burgos G.
        Glutamate receptor subtypes mediating synaptic activation of prefrontal cortex neurons: Relevance for schizophrenia.
        J Neurosci. 2011; 31: 142-156
        • Caputi A.
        • Fuchs E.C.
        • Allen K.
        • Le M.C.
        • Monyer H.
        Selective reduction of AMPA currents onto hippocampal interneurons impairs network oscillatory activity.
        PLoS One. 2012; 7e37318
        • Matta J.A.
        • Pelkey K.A.
        • Craig M.T.
        • Chittajallu R.
        • Jeffries B.W.
        • McBain C.J.
        Developmental origin dictates interneuron AMPA and NMDA receptor subunit composition and plasticity.
        Nat Neurosci. 2013; 16: 1032-1041
        • Le Roux N.
        • Cabezas C.
        • Böhm U.L.
        • Poncer J.C.
        Input-specific learning rules at excitatory synapses onto hippocampal parvalbumin-expressing interneurons.
        J Physiol. 2013; 591: 1809-1822
        • Kloc M.
        • Maffei A.
        Target-specific properties of thalamocortical synapses onto layer 4 of mouse primary visual cortex.
        J Neurosci. 2014; 34: 15455-15465
        • Lalanne T.
        • Oyrer J.
        • Mancino A.
        • Gregor E.
        • Chung A.
        • Huynh L.
        • et al.
        Synapse-specific expression of calcium-permeable AMPA receptors in neocortical layer 5.
        J Physiol. 2016; 594: 837-861
        • McGarry L.M.
        • Carter A.G.
        Inhibitory gating of basolateral amygdala inputs to the prefrontal cortex.
        J Neurosci. 2016; 36: 9391-9406
        • Mierau S.B.
        • Patrizi A.
        • Hensch T.K.
        • Fagiolini M.
        Cell-specific regulation of N-methyl-D-aspartate receptor maturation by Mecp2 in cortical circuits.
        Biol Psychiatry. 2016; 79: 746-754
        • Karayannis T.
        • Huerta-Ocampo I.
        • Capogna M.
        GABAergic and pyramidal neurons of deep cortical layers directly receive and differently integrate callosal input.
        Cereb Cortex. 2007; 17: 1213-1226
        • Liu H.
        • Mantyh P.W.
        • Basbaum A.I.
        NMDA-receptor regulation of substance P release from primary afferent nociceptors.
        Nature. 1997; 386: 721-724
        • Larsen R.S.
        • Corlew R.J.
        • Henson M.A.
        • Roberts A.C.
        • Mishina M.
        • Watanabe M.
        • et al.
        NR3A-containing NMDARs promote neurotransmitter release and spike timing-dependent plasticity.
        Nat Neurosci. 2011; 14: 338-344
        • Buchanan K.A.
        • Blackman A.V.
        • Moreau A.W.
        • Elgar D.
        • Costa R.P.
        • Lalanne T.
        • et al.
        Target-specific expression of presynaptic NMDA receptors in neocortical microcircuits.
        Neuron. 2012; 75: 451-466
        • Abrahamsson T.
        • Chou C.Y.C.
        • Li S.Y.
        • Mancino A.
        • Costa R.P.
        • Brock J.A.
        • et al.
        Differential regulation of evoked and spontaneous release by presynaptic NMDA receptors.
        Neuron. 2017; 96: 839-855
        • Bouvier G.
        • Bidoret C.
        • Casado M.
        • Paoletti P.
        Presynaptic NMDA receptors: Roles and rules.
        Neuroscience. 2015; 311: 322-340
        • Banerjee A.
        • Larsen R.S.
        • Philpot B.D.
        • Paulsen O.
        Roles of Presynaptic NMDA receptors in neurotransmission and plasticity.
        Trends Neurosci. 2016; 39: 26-39
        • DeBiasi S.
        • Minelli A.
        • Melone M.
        • Conti F.
        Presynaptic NMDA receptors in the neocortex are both auto- and heteroreceptors.
        NeuroReport. 1996; 7: 2773-2776
        • Conti F.
        • Barbaresi P.
        • Melone M.
        • Ducati A.
        Neuronal and glial localization of NR1 and NR2A/B subunits of the NMDA receptor in the human cerebral cortex.
        Cereb Cortex. 1999; 9: 110-120
        • Chattopadhyaya B.
        • Di C.G.
        • Higashiyama H.
        • Knott G.W.
        • Kuhlman S.J.
        • Welker E.
        • et al.
        Experience and activity-dependent maturation of perisomatic GABAergic innervation in primary visual cortex during a postnatal critical period.
        J Neurosci. 2004; 24: 9598-9611
        • Pafundo D.E.
        • Miyamae T.
        • Lewis D.A.
        • Gonzalez-Burgos G.
        Cholinergic modulation of neuronal excitability and recurrent excitation–inhibition in prefrontal cortex circuits: Implications for gamma oscillations.
        J Physiol. 2013; 591: 4725-4728
        • Miyamae T.
        • Chen K.
        • Lewis D.A.
        • Gonzalez Burgos G.
        Distinct physiological maturation of parvalbumin-positive neuron subtypes in mouse prefrontal cortex.
        J Neurosci. 2017; 37: 4883-4902
        • Kraushaar U.
        • Jonas P.
        Efficacy and stability of quantal GABA release at a hippocampal interneuron–principal neuron synapse.
        J Neurosci. 2000; 20: 5594-5607
        • Lanore F.
        • Angus Silver R.
        Extracting quantal properties of transmission at central synapses.
        in: Korngreen A. Advanced Patch-Clamp Analysis for Neuroscientists. Springer, New York2016: 193-211
        • Sippy T.
        • Yuste R.
        Decorrelating action of inhibition in neocortical networks.
        J Neurosci. 2013; 33: 9813-9830
        • Szabadics J.
        • Varga C.
        • Molnar G.
        • Olah S.
        • Barzo P.
        • Tamas G.
        Excitatory effect of GABAergic axo-axonic cells in cortical microcircuits.
        Science. 2006; 311: 233-235
        • Woodruff A.R.
        • McGarry L.M.
        • Vogels T.P.
        • Inan M.
        • Anderson S.A.
        • Yuste R.
        State-dependent function of neocortical chandelier cells.
        J Neurosci. 2011; 31: 17872-17886
        • Corlew R.
        • Wang Y.
        • Ghermazien H.
        • Erisir A.
        • Philpot B.D.
        Developmental switch in the contribution of presynaptic and postsynaptic NMDA receptors to long-term depression.
        J Neurosci. 2007; 27: 9835-9845
        • Tseng K.Y.
        • O’Donnell P.
        Post-pubertal emergence of prefrontal cortical up states induced by D1-NMDA co-activation.
        Cereb Cortex. 2005; 15: 49-57
        • Szabadits E.
        • Cserep C.
        • Szonyi A.
        • Fukazawa Y.
        • Shigemoto R.
        • Watanabe M.
        • et al.
        NMDA receptors in hippocampal GABAergic synapses and their role in nitric oxide signaling.
        J Neurosci. 2011; 31: 5893-5904
        • Chisari M.
        • Zorumski C.F.
        • Mennerick S.
        Cross talk between synaptic receptors mediates NMDA-induced suppression of inhibition.
        J Neurophysiol. 2012; 107: 2532-2540
        • Hefft S.
        • Kraushaar U.
        • Geiger J.R.
        • Jonas P.
        Presynaptic short-term depression is maintained during regulation of transmitter release at a GABAergic synapse in rat hippocampus.
        J Physiol. 2002; 539: 201-208
        • Hogan-Cann A.D.
        • Anderson C.M.
        Physiological roles of non-neuronal NMDA receptors.
        Trends Pharmacol Sci. 2016; 37: 750-767
        • Freund T.F.
        • Katona I.
        Perisomatic inhibition.
        Neuron. 2007; 56: 33-42
        • Kruglikov I.
        • Rudy B.
        Perisomatic GABA release and thalamocortical integration onto neocortical excitatory cells are regulated by neuromodulators.
        Neuron. 2008; 58: 911-924
        • Gonzalez-Burgos G.
        • Miyamae T.
        • Pafundo D.E.
        • Yoshino H.
        • Rotaru D.C.
        • Hoftman G.
        • et al.
        Functional maturation of GABA synapses during postnatal development of the monkey dorsolateral prefrontal cortex.
        Cereb Cortex. 2015; 25: 4076-4093
        • Hefft S.
        • Jonas P.
        Asynchronous GABA release generates long-lasting inhibition at a hippocampal interneuron–principal neuron synapse.
        Nat Neurosci. 2005; 8: 1319-1328
        • Zaitsev A.V.
        • Povysheva N.V.
        • Lewis D.A.
        • Krimer L.S.
        P/Q-type, but not N-type, calcium channels mediate GABA release from fast-spiking interneurons to pyramidal cells in rat prefrontal cortex.
        J Neurophysiol. 2007; 97: 3567-3573
        • Galarreta M.
        • Erdelyi F.
        • Szabo G.
        • Hestrin S.
        Cannabinoid sensitivity and synaptic properties of 2 GABAergic networks in the neocortex.
        Cereb Cortex. 2008; 18: 2296-2305
        • Mathew S.S.
        • Hablitz J.J.
        Presynaptic NMDA receptors mediate IPSC potentiation at GABAergic synapses in developing rat neocortex.
        PLoS One. 2011; 6e17311
        • Csicsvari J.
        • Jamieson B.
        • Wise K.D.
        • Buzsaki G.
        Mechanisms of gamma oscillations in the hippocampus of the behaving rat.
        Neuron. 2003; 37: 311-322
        • Hajos N.
        • Palhalmi J.
        • Mann E.O.
        • Nemeth B.
        • Paulsen O.
        • Freund T.F.
        Spike timing of distinct types of GABAergic interneuron during hippocampal gamma oscillations in vitro.
        J Neurosci. 2004; 24: 9127-9137
        • Massi L.
        • Lagler M.
        • Hartwich K.
        • Borhegyi Z.
        • Somogyi P.
        • Klausberger T.
        Temporal dynamics of parvalbumin-expressing axo-axonic and basket cells in the rat medial prefrontal cortex in vivo.
        J Neurosci. 2012; 32: 16496-16502
        • Kim D.
        • Jeong H.
        • Lee J.
        • Ghim J.W.
        • Her E.S.
        • Lee S.H.
        • et al.
        Distinct roles of parvalbumin- and somatostatin-expressing interneurons in working memory.
        Neuron. 2016; 92: 902-915
        • Lisman J.E.
        • Fellous J.M.
        • Wang X.J.
        A role for NMDA-receptor channels in working memory.
        Nat Neurosci. 1998; 1: 273-275
        • Wang X.J.
        Neurophysiological and computational principles of cortical rhythms in cognition.
        Physiol Rev. 2010; 90: 1195-1268
        • Wang M.
        • Yang Y.
        • Wang C.J.
        • Gamo N.J.
        • Jin L.E.
        • Mazer J.A.
        • et al.
        NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex.
        Neuron. 2013; 77: 736-749
        • Kamigaki T.
        • Dan Y.
        Delay activity of specific prefrontal interneuron subtypes modulates memory-guided behavior.
        Nat Neurosci. 2017; 20: 854-863
        • Verma A.
        • Moghaddam B.
        NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: Modulation by dopamine.
        J Neurosci. 1996; 16: 373-379
        • Auger M.L.
        • Floresco S.B.
        Prefrontal cortical GABAergic and NMDA glutamatergic regulation of delayed responding.
        Neuropharmacology. 2017; 113: 10-20
        • Carr D.B.
        • Sesack S.R.
        Hippocampal afferents to the rat prefrontal cortex: Synaptic targets and relation to dopamine terminals.
        J Comp Neurol. 1996; 369: 1-15
        • Gabbott P.
        • Headlam A.
        • Busby S.
        Morphological evidence that CA1 hippocampal afferents monosynaptically innervate PV-containing neurons and NADPH-diaphorase reactive cells in the medial prefrontal cortex (areas 25/32) of the rat.
        Brain Res. 2002; 946: 314-322
        • Rotaru D.C.
        • Barrionuevo G.
        • Sesack S.R.
        Mediodorsal thalamic afferents to layer III of the rat prefrontal cortex: Synaptic relationships to subclasses of interneurons.
        J Comp Neurol. 2005; 490: 220-238
        • Dilgen J.
        • Tejeda H.A.
        • O’Donnell P.
        Amygdala inputs drive feedforward inhibition in the medial prefrontal cortex.
        J Neurophysiol. 2013; 110: 221-229
        • Spellman T.
        • Rigotti M.
        • Ahmari S.E.
        • Fusi S.
        • Gogos J.A.
        • Gordon J.A.
        Hippocampal–prefrontal input supports spatial encoding in working memory.
        Nature. 2015; 522: 309-314
        • Fujisawa S.
        • Buzsaki G.
        A 4 Hz oscillation adaptively synchronizes prefrontal, VTA, and hippocampal activities.
        Neuron. 2011; 72: 153-165
        • Isaacson J.S.
        • Scanziani M.
        How inhibition shapes cortical activity.
        Neuron. 2011; 72: 231-243
        • Ma Y.
        • Hu H.
        • Berrebi A.S.
        • Mathers P.H.
        • Agmon A.
        Distinct subtypes of somatostatin-containing neocortical interneurons revealed in transgenic mice.
        J Neurosci. 2006; 26: 5069-5082
        • Lovett-Barron M.
        • Turi G.F.
        • Kaifosh P.
        • Lee P.H.
        • Bolze F.
        • Sun X.H.
        • et al.
        Regulation of neuronal input transformations by tunable dendritic inhibition.
        Nat Neurosci. 2012; 15: 423-430
        • Tremblay R.
        • Lee S.
        • Rudy B.
        GABAergic interneurons in the neocortex: From cellular properties to circuits.
        Neuron. 2016; 91: 260-292
        • Veit J.
        • Hakim R.
        • Jadi M.P.
        • Sejnowski T.J.
        • Adesnik H.
        Cortical gamma band synchronization through somatostatin interneurons.
        Nat Neurosci. 2017; 20: 951-959
        • Krystal J.H.
        • Anticevic A.
        • Yang G.J.
        • Dragoi G.
        • Driesen N.R.
        • Wang X.J.
        • et al.
        Impaired tuning of neural ensembles and the pathophysiology of schizophrenia: A translational and computational neuroscience perspective.
        Biol Psychiatry. 2017; 81: 874-885
        • Bitanihirwe B.K.
        • Lim M.P.
        • Kelley J.F.
        • Kaneko T.
        • Woo T.U.
        Glutamatergic deficits and parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia.
        BMC Psychiatry. 2009; 9: 71
        • Enwright III, J.F.
        • Huo Z.
        • Arion D.
        • Corradi J.P.
        • Tseng G.
        • Lewis D.A.
        Transcriptome alterations of prefrontal cortical parvalbumin neurons in schizophrenia.
        Mol Psychiatry. 2017; ([published online ahead of print Nov 7])
        • Saunders J.A.
        • Tatard-Leitman V.M.
        • Suh J.
        • Billingslea E.N.
        • Roberts T.P.
        • Siegel S.J.
        Knockout of NMDA receptors in parvalbumin interneurons recreates autism-like phenotypes.
        Autism Res. 2013; 6: 69-77
        • Billingslea E.N.
        • Tatard-Leitman V.M.
        • Anguiano J.
        • Jutzeler C.R.
        • Suh J.
        • Saunders J.A.
        • et al.
        Parvalbumin cell ablation of NMDA-R1 causes increased resting network excitability with associated social and self-care deficits.
        Neuropsychopharmacology. 2014; 39: 1603-1613
        • Vullhorst D.
        • Mitchell R.M.
        • Keating C.
        • Roychowdhury S.
        • Karavanova I.
        • Tao-Cheng J.H.
        • et al.
        A negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling.
        Nat Commun. 2015; 6: 7222
        • Bygrave A.M.
        • Masiulis S.
        • Nicholson E.
        • Berkemann M.
        • Barkus C.
        • Sprengel R.
        • et al.
        Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801.
        Transl Psychiatry. 2016; 6: e778
        • Nakazawa K.
        • Jeevakumar V.
        • Nakao K.
        Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia.
        NPJ Schizophr. 2017; 3: 7

      Linked Article

      • Defining the Role of Interneuron N-Methyl-D-Aspartate Receptors in Prefrontal Cortex Inhibition
        Biological PsychiatryVol. 84Issue 6
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          Sustained pharmacological activation of the N-methyl-D-aspartate receptor (NMDAR) has long been known for its neurotoxic effects (1). Nevertheless, exposure in vivo to NMDAR antagonists also shows striking neurotoxicity resulting in cell death in localized regions of the neocortex (the retrosplenial cortex in particular) (2). Because it appeared that neurotoxicity was mediated by an excitotoxic action, the NMDAR antagonist action was attributed to a disinhibition that could be ameliorated by the cholinergic blockade.
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