Skip to main content

Advertisement

Log in

Comparison of the effects of acute and chronic administration of ketamine on hippocampal oscillations: relevance for the NMDA receptor hypofunction model of schizophrenia

  • Original Article
  • Published:
Brain Structure and Function Aims and scope Submit manuscript

Abstract

The proper organization and function of GABAergic interneuron networks is essential for many cognitive processes and abnormalities in these systems have been documented in schizophrenic patients. The memory function of the hippocampus depends on two major patterns of oscillations in the theta and gamma ranges, both requiring the intact functioning of the network of fast-firing interneurons expressing parvalbumin. We examined the ability of acute and chronic administration of NMDA receptor (NMDA-R) antagonists to recapitulate the oscillatory dysfunctions observed in schizophrenia. In freely moving rats, acute injection of MK801 or ketamine increased gamma power in both CA1 and dentate gyrus of the hippocampus. Theta peak shifted to higher frequencies whereas the average 5–10 Hz theta power decreased by 24% in CA1 and remained high in the dentate gyrus. Strong increase in CA1 gamma and decrease in theta power triggered by brainstem stimulation were found under urethane anesthesia. In contrast to acute experiments, chronic administration of ketamine caused a steady decline in both gamma and theta oscillations, 2–4 weeks after treatment. A further important difference between the two models was that the effects of acute injection were more robust than the changes after chronic treatment. Chronic administration of ketamine also leads to decrease in the number of detectable parvalbumin interneurons. Histological examination of interindividual differences indicated, however, that within the ketamine treated group a further decrease in parvalbumin neurons correlated with strengthening of oscillations. The findings are consistent with abnormalities of oscillations in human schizophrenia and further validate the NMDA-R hypofunction hypothesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Adler CM, Malhotra AK, Elman I, Goldberg T, Egan M, Pickar D, Breier A (1999) Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiatry 156:1646–1649

    PubMed  CAS  Google Scholar 

  • Baldeweg T, Spence S, Hirsch SR, Gruzelier J (1998) Gamma-band electroencephalographic oscillations in a patient with somatic hallucinations. Lancet 352:620–621

    Article  PubMed  CAS  Google Scholar 

  • Becker A, Grecksch G (2004) Ketamine-induced changes in rat behaviour: a possible animal model of schizophrenia. Test of predictive validity. Prog Neuropsychopharmacol Biol Psychiatry 28:1267–1277

    Article  PubMed  CAS  Google Scholar 

  • Becker A, Peters B, Schroeder H, Mann T, Huether G, Grecksch G (2003) Ketamine-induced changes in rat behaviour: a possible animal model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27:687–700

    Article  PubMed  CAS  Google Scholar 

  • Benes FM, Kwok EW, Vincent SL, Todtenkopf MS (1998) A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol Psychiatry 44:88–97

    Article  PubMed  CAS  Google Scholar 

  • Benneyworth MA, Roseman AS, Basu AC, Coyle JT (2011) Failure of NMDA receptor hypofunction to induce a pathological reduction in PV-positive GABAergic cell markers. Neurosci Lett 488:267–271

    Article  PubMed  CAS  Google Scholar 

  • Berretta S, Lange N, Bhattacharyya S, Sebro R, Garces J, Benes FM (2004) Long-term effects of amygdala GABA receptor blockade on specific subpopulations of hippocampal interneurons. Hippocampus 14:876–894

    Google Scholar 

  • Bland BH (1986) Physiology and pharmacology of hippocampal formation theta rhythms. Prog Neurobiol 26:1–54

    Article  PubMed  CAS  Google Scholar 

  • Bragin A, Jando G, Nadasdy Z, Hetke J, Wise K, Buzsaki G (1995) Gamma (40–100 Hz) oscillation in the hippocampus of the behaving rat. J Neurosci 15:47–60

    PubMed  CAS  Google Scholar 

  • Braun I, Genius J, Grunze H, Bender A, Moller HJ, Rujescu D (2007) Alterations of hippocampal and prefrontal GABAergic interneurons in an animal model of psychosis induced by NMDA receptor antagonism. Schizophr Res 97:254–263

    Article  PubMed  Google Scholar 

  • Buhl EH, Szilagyi T, Halasy K, Somogyi P (1996) Physiological properties of anatomically identified basket and bistratified cells in the CA1 area of the rat hippocampus in vitro. Hippocampus 6:294–305

    Article  PubMed  CAS  Google Scholar 

  • Buhl EH, Han ZS, Lorinczi Z, Stezhka VV, Karnup SV, Somogyi P (1994) Physiological properties of anatomically identified axo-axonic cells in the rat hippocampus. J Neurophysiol 71:1289–1307

    PubMed  CAS  Google Scholar 

  • Buzsaki G (2002) Theta oscillations in the hippocampus. Neuron 33:325–340

    Article  PubMed  CAS  Google Scholar 

  • Buzsaki G, Draguhn A (2004) Neuronal oscillations in cortical networks. Science 304:1926–1929

    Article  PubMed  CAS  Google Scholar 

  • Buzsaki G, Czopf J, Kondakor ILK (1986) Laminar distribution of hippocampal rhythmic slow activity (RSA) in the behaving rat: current source density analysis. Brain Res 365:125–137

    Article  PubMed  CAS  Google Scholar 

  • Buzsaki G, Horvath Z, Urioste R, Hetke J, Wise K (1992) High-frequency network oscillation in the hippocampus. Science 256:1025–1027

    Article  PubMed  CAS  Google Scholar 

  • Carlen M, Meletis K, Siegle JH, Cardin JA, Futai K, Vierling-Claassen D, Ruhlmann C, Jones SR, Deisseroth K, Sheng M, Moore CI, Tsai LH (2011) A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior. Mol Psychiatry (epub ahead of print)

  • Csicsvari J, Hirase H, Czurkó A, Mamiya A, Buzsaki G (1999) Oscillatory coupling of hippocampal pyramidal cells and interneurons in the behaving rat. J Neurosci 19:274–287

    PubMed  CAS  Google Scholar 

  • Gao XM, Sakai K, Roberts RC, Conley RR, Dean B, Tamminga CA (2000) Ionotropic glutamate receptors and expression of N-methyl-d-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia. Am J Psychiatry 157:1141–1149

    Article  PubMed  CAS  Google Scholar 

  • Gillies MJ, Traub RD, LeBleau FEN, Davies CH, Gloveli T, Buhl EH, Whittington MA (2002) A model of atropine-resistant theta oscillations in rat hippocampal area CA1. J Physiol (London) 543:779–793

    Article  CAS  Google Scholar 

  • Goff DC, Coyle JT (2001) The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 158:1367–1377

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Burgos G, Lewis DA (2008) GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia. Schizophr Bull 34:944–961

    Article  PubMed  Google Scholar 

  • Grunze HC, Rainnie DG, Hasselmo ME, Barkai E, Hearn EF, McCarley RW, Greene RW (1996) NMDA-dependent modulation of CA1 local circuit inhibition. J Neurosci 16:2034–2043

    PubMed  CAS  Google Scholar 

  • Hajos M, Hoffman WE, Kocsis B (2008) Activation of cannabinoid-1 receptors disrupts sensory gating and neuronal oscillations: relevance to schizophrenia. Biol Psychiatry 63:1075–1083

    Article  PubMed  CAS  Google Scholar 

  • Hajos N, Freund TF, Mody I (2002) Comparison of single NMDA receptor channels recorded on hippocampal principal cells and oriens/alveus interneurons projecting to stratum lacunosum-moleculare (O-LM cells). Acta Biol Hung 53:465–472

    Article  PubMed  CAS  Google Scholar 

  • Hakami T, Jones NC, Tolmacheva EA, Gaudias J, Chaumont J, Salzberg M, O’Brien TJ, Pinault D (2009) NMDA receptor hypofunction leads to generalized and persistent aberrant gamma oscillations independent of hyperlocomotion and the state of consciousness. PLoS One 4:e6755

    Article  PubMed  Google Scholar 

  • Harte MK, Powell SB, Swerdlow NR, Geyer MA, Reynolds GP (2007) Deficits in parvalbumin and calbindin immunoreactive cells in the hippocampus of isolation reared rats. J Neural Transm 114:893–898

    Article  PubMed  CAS  Google Scholar 

  • Hong LE, Summerfelt A, Buchanan RW, O’Donnell P, Thaker GK, Weiler MA, Lahti AC (2010) Gamma and delta neural oscillations and association with clinical symptoms under subanesthetic ketamine. Neuropsychopharmacology 35:632–640

    Article  PubMed  Google Scholar 

  • Javitt DC, Zukin SR (1990) The role of excitatory amino acids in neuropsychiatric illness. J Neuropsychiatry Clin Neurosci 2:44–52

    PubMed  CAS  Google Scholar 

  • Javitt DC, Doneshka P, Grochowski S, Ritter W (1995) Impaired mismatch negativity generation reflects widespread dysfunction of working memory in schizophrenia. Arch Gen Psychiatry 52:550–558

    Article  PubMed  CAS  Google Scholar 

  • Javitt DC, Steinschneider M, Schroeder CE, Arezzo JC (1996) Role of cortical N-methyl-d-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia. Proc Natl Acad Sci USA 93:11962–11967

    Article  PubMed  CAS  Google Scholar 

  • Kantrowitz JT, Javitt DC (2010) N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull 83:108–121

    Article  PubMed  CAS  Google Scholar 

  • Keilhoff G, Becker A, Grecksch G, Wolf G, Bernstein HG (2004) Repeated application of ketamine to rats induces changes in the hippocampal expression of parvalbumin, neuronal nitric oxide synthase and cFOS similar to those found in human schizophrenia. Neuroscience 126:591–598

    Article  PubMed  CAS  Google Scholar 

  • Kilts CD (2002) The changing roles and targets for animal models of schizophrenia. Biol Psychiatry 50:845–855

    Article  Google Scholar 

  • Kinney GG, Kocsis B, Vertes RP (1994) Injections of excitatory amino acid antagonists into the median raphe nucleus produce hippocampal theta rhythm in the urethane-anesthetized rat. Brain Res 654:96–104

    Article  PubMed  CAS  Google Scholar 

  • Kinney JW, Davis CN, Tabarean I, Conti B, Bartfai T, Behrens MM (2006) A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons. J Neurosci 26:1604–1615

    Article  PubMed  CAS  Google Scholar 

  • Klausberger T, Magill PJ, Marton LF, Roberts DB, Cobden PM, Buzsaki G, Somogyi P (2003) Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo. Nature 421:844–848

    Article  PubMed  CAS  Google Scholar 

  • Kocsis B (2011) Differential role of NR2A and NR2B subunits in NMDA receptor antagonist-induced aberrant cortical gamma oscillations. Biol Psychiatry (in press)

  • Kocsis B, Li S (2004) In vivo contribution of h-channels in the septal pacemaker to the generation of theta rhythm in the rat. Eur J Neurosci 20:2149–2158

    Article  PubMed  Google Scholar 

  • Kocsis B, Bragin A, Buzsaki G (1999) Interdependence of multiple theta generators in the hippocampus: a partial coherence analysis. J Neurosci 19:6200–6212

    PubMed  CAS  Google Scholar 

  • Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214

    Article  PubMed  CAS  Google Scholar 

  • Lakatos P, Karmos G, Mehta AD, Ulbert I, Schroeder CE (2008) Entrainment of neuronal oscillations as a mechanism of attentional selection. Science 320:110–113

    Article  PubMed  CAS  Google Scholar 

  • Lanre-Amos T, Kocsis B (2010) Hippocampal oscillations in the rodent model of schizophrenia induced by amygdala GABA receptor blockade. Front Psychiatry 1:132

    PubMed  CAS  Google Scholar 

  • Lazarewicz MT, Ehrlichman RS, Maxwell CR, Gandal MJ, Finkel LH, Siegel SJ (2010) Ketamine modulates theta and gamma oscillations. J Cogn Neurosci 22:1452–1464

    Article  PubMed  Google Scholar 

  • Lewis DA, Hashimoto T, Volk DW (2005a) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6:312–324

    Article  PubMed  CAS  Google Scholar 

  • Lisman J, Buzsaki G (2008) A neural coding scheme formed by the combined function of gamma and theta oscillations. Schizophr Bull 34:974–980

    Article  PubMed  Google Scholar 

  • Lisman JE, Coyle JT, Green RW, Javitt DC, Benes FM, Heckers S, Grace AA (2008) Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci 31:234–242

    Article  PubMed  CAS  Google Scholar 

  • Lodge DJ, Behrens MM, Grace AA (2009) A loss of parvalbumin-containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia. J Neurosci 29:2344–2354

    Article  PubMed  CAS  Google Scholar 

  • Ma J, Leung LS (2007) The supramammillo-septal-hippocampal pathway mediates sensorimotor gating impairment and hyperlocomotion induced by MK-801 and ketamine in rats. Psychopharmacology (Berl) 191:961–974

    Article  CAS  Google Scholar 

  • Manahan-Vaughan D, von Haebler D, Winter C, Juckel G, Heinemann U (2008) A single application of MK801 causes symptoms of acute psychosis, deficits in spatial memory, and impairment of synaptic plasticity in rats. Hippocampus 18:125–134

    Article  PubMed  CAS  Google Scholar 

  • Mansbach RS, Geyer MA (1989) Effects of phencyclidine and phencyclidine biologs on sensorimotor gating in the rat. Neuropsychopharmacology 2:299–308

    Article  PubMed  CAS  Google Scholar 

  • Marcotte ER, Pearson DM, Srivastava LK (2001) Animal models of schizophrenia: a critical review. J Psychiatry Neurosci 26:395–410

    PubMed  CAS  Google Scholar 

  • Meador-Woodruff JH, Healy DJ (2000) Glutamate receptor expression in schizophrenic brain. Brain Res Brain Res Rev 31:288–294

    Article  PubMed  CAS  Google Scholar 

  • Medoff DR, Holcomb HH, Lahti AC, Tamminga CA (2001) Probing the human hippocampus using rCBF: contrasts in schizophrenia. Hippocampus 11:543–550

    Article  PubMed  CAS  Google Scholar 

  • Middleton S, Jalics J, Kispersky T, Lebeau FE, Roopun AK, Kopell NJ, Whittington MA, Cunningham MO (2008) NMDA receptor-dependent switching between different gamma rhythm-generating microcircuits in entorhinal cortex. Proc Natl Acad Sci USA 105:18572–18577

    Article  PubMed  CAS  Google Scholar 

  • Moghaddam B (2003) Bringing order to the glutamate chaos in schizophrenia. Neuron 40:881–884

    Article  PubMed  CAS  Google Scholar 

  • Moghaddam B, Jackson ME (2003) Glutamatergic animal models of schizophrenia. Ann N Y Acad Sci 1003:131–137

    Article  PubMed  CAS  Google Scholar 

  • Montgomery SM, Betancur MI, Buzsaki G (2009) Behavior-dependent coordination of multiple theta dipoles in the hippocampus. J Neurosci 29:1381–1394

    Article  PubMed  CAS  Google Scholar 

  • Moore H, Jentsch JD, Ghajarnia ME, Geyer MA, Grace AA (2006) A neurobehavioral systems analysis of the effects of gestational exposure to methylazoxymethanol acetate (MAM) in the rat: implications for the neuropathology of schizophrenia. Biol Psychiatry 60:253–264

    Article  PubMed  CAS  Google Scholar 

  • Morrow BA, Elsworth JD, Roth RH (2007) Repeated phencyclidine in monkeys results in loss of parvalbumin-containing axo-axonic projections in the prefrontal cortex. Psychopharmacology (Berl) 192:283–290

    Article  CAS  Google Scholar 

  • Nyiri G, Stephenson FA, Freund TF, Somogyi P (2003) Large variability in synaptic N-methyl-d-aspartate receptor density on interneurons and a comparison with pyramidal-cell spines in the rat hippocampus. Neuroscience 119:347–363

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Elsevier Academic Press, Amsterdam

  • Pinault D (2008) N-methyl-d-aspartate receptor antagonists ketamine and MK-801 induce wake-related aberrant gamma oscillations in the rat neocortex. Biol Psychiatry 63:730–735

    Article  PubMed  CAS  Google Scholar 

  • Plourde G, Baribeau J, Bonhomme V (1997) Ketamine increases the amplitude of the 40-Hz auditory steady-state response in humans. Br J Anaesth 78:524–529

    PubMed  CAS  Google Scholar 

  • Reynolds GP, Abdul-Monim Z, Neill JC, Zhang ZJ (2004) Calcium binding protein markers of GABA deficits in schizophrenia—postmortem studies and animal models. Neurotox Res 6:57–61

    Article  PubMed  Google Scholar 

  • Rujescu D, Bender A, Keck M, Hartmann AM, Ohl F, Raeder H, Giegling I, Genius J, McCarley RW, Moller HJ, Grunze H (2006) A pharmacological model for psychosis based on N-methyl-d-aspartate receptor hypofunction: molecular, cellular, functional and behavioral abnormalities. Biol Psychiatry 59:721–729

    Article  PubMed  CAS  Google Scholar 

  • Spencer KM, Niznikiewicz MA, Nestor PG, Shenton ME, McCarley RW (2009) Left auditory cortex gamma synchronization and auditory hallucination symptoms in schizophrenia. BMC Neurosci 10:85

    Article  PubMed  Google Scholar 

  • Stefani MR, Moghaddam B (2005) Transient N-methyl-d-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia. Biol Psychiatry 57:433–436

    Article  PubMed  CAS  Google Scholar 

  • Tamminga CA, Stan AD, Wagner AD (2010) The hippocampal formation in schizophrenia. Am J Psychiatry 167:1178–1193

    Article  PubMed  Google Scholar 

  • Todtenkopf MS, Benes FM (1998) Distribution of glutamate decarboxylase65 immunoreactive puncta on pyramidal and nonpyramidal neurons in hippocampus of schizophrenic brain. Synapse 29:323–332

    Article  PubMed  CAS  Google Scholar 

  • Tort AB, Rotstein HG, Dugladze T, Gloveli T, Kopell NJ (2007) On the formation of gamma-coherent cell assemblies by oriens lacunosum-moleculare interneurons in the hippocampus. Proc Natl Acad Sci USA 104:13490–13495

    Article  PubMed  CAS  Google Scholar 

  • Tseng KY, Lewis BL, Hashimoto T, Sesack SR, Kloc M, Lewis DA, O’Donnell P (2008) A neonatal ventral hippocampal lesion causes functional deficits in adult prefrontal cortical interneurons. J Neurosci 28:12691–12699

    Article  PubMed  CAS  Google Scholar 

  • Uhlhaas PJ, Singer W (2010) Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci 11:100–113

    Article  PubMed  CAS  Google Scholar 

  • Vertes RP, Kocsis B (1997) Brainstem-diencephalo-septohippocampal systems controlling the theta rhythm of the hippocampus. Neuroscience 81:893–926

    Article  PubMed  CAS  Google Scholar 

  • Vohs JL, Chambers RA, Krishnan GP, O’Donnell BF, Berg S, Morzorati SL (2010) GABAergic modulation of the 40 Hz auditory steady-state response in a rat model of schizophrenia. Int J Neuropsychopharmacol 13:487–497

    Article  PubMed  CAS  Google Scholar 

  • Vreugdenhil M, Jefferys JG, Celio MR, Schwaller B (2003) Parvalbumin-deficiency facilitates repetitive IPSCs and gamma oscillations in the hippocampus. J Neurophysiol 89:1414–1422

    Article  PubMed  Google Scholar 

  • Wang XJ (2010) Neurophysiological and computational principles of cortical rhythms in cognition. Physiol Rev 90:1195–1268

    Article  PubMed  Google Scholar 

  • Wen L, Lu YS, Zhu XH, Li XM, Woo RS, Chen YJ, Yin DM, Lai C, Terry AV Jr, Vazdarjanova A, Xiong WC, Mei L (2010) Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc Natl Acad Sci USA 107:1211–1216

    Article  PubMed  CAS  Google Scholar 

  • Woo TU, Walsh JP, Benes FM (2004) Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-d-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder. Arch Gen Psychiatry 61:649–657

    Article  PubMed  CAS  Google Scholar 

  • Xi D, Zhang W, Wang HX, Stradtman GG, Gao WJ (2009) Dizocilpine (MK-801) induces distinct changes of N-methyl-d-aspartic acid receptor subunits in parvalbumin-containing interneurons in young adult rat prefrontal cortex. Int J Neuropsychopharmacol 12:1395–1408

    Article  PubMed  CAS  Google Scholar 

  • Young JW, Powell SB, Risbrough V, Marston HM, Geyer MA (2009) Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia. Pharmacol Ther 122:150–202

    Article  PubMed  CAS  Google Scholar 

  • Zhang ZJ, Reynolds GP (2002) A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr Res 55:1–10

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by National Institute of Health Grants MH0083199 and by an investigator-initiated unrestricted grant by Sepracor, Inc.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bernat Kocsis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kittelberger, K., Hur, E.E., Sazegar, S. et al. Comparison of the effects of acute and chronic administration of ketamine on hippocampal oscillations: relevance for the NMDA receptor hypofunction model of schizophrenia. Brain Struct Funct 217, 395–409 (2012). https://doi.org/10.1007/s00429-011-0351-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00429-011-0351-8

Keywords

Navigation