Flexible behavior in dynamic, real-world environments requires more than static spatial learning and memory. Discordant and unstable cues must be organized in coherent subsets to give rise to meaningful spatial representations. We model this form of cognitive coordination on a rotating arena - Carousel where arena- and room-bound spatial cues are dissociated. Hippocampal neuronal ensemble activity can repeatedly switch between multiple representations of such an environment. Injection of tetrodotoxin into one hippocampus prevents cognitive coordination during avoidance of a stationary room-defined place on the Carousel and increases coactivity of previously unrelated neurons in the uninjected hippocampus. Place avoidance on the Carousel is impaired after systemic administration of non-competitive NMDAr blockers (MK-801) used to model schizophrenia in animals and people. We tested if this effect is due to cognitive disorganization or other effect of NMDAr antagonism such as hyperlocomotion, spatial memory impairment, or general learning deficit. We also examined if the same dose of MK-801 alters patterns of immediate-early gene (IEG) expression in the hippocampus. IEG expression is triggered in neuronal nuclei in a context-specific manner after behavioral exploration and it is used to map activity in neuronal populations. IEG expression is critical for maintenance of synaptic plasticity and memory consolidation. We show that the same dose of MK-801 that impairs spatial coordination of rats on the Carousel also eliminates contextual specificity of IEG expression in hippocampal CA1 ensembles. This effect is due to increased similarity between ensembles activated in different environments, consistent with the idea that it is caused by increased coactivity between neurons, which did not previously fire together. Our data support the proposition of the Hypersynchrony theory that cognitive disorganization in psychosis is due to increased coactivity between unrelated neurons.

Neurophysiology of Memory Institute of Physiology Academy of Sciences of the Czech Republic Prague Czech Republic

Zobrazit více v PubMed

Adell A., Jiménez-Sánchez L., López-Gil X., Romón T. (2012). Is the acute NMDA receptor hypofunction a valid model of schizophrenia? Schizophr. Bull. 38, 9–1410.1093/schbul/sbr133 PubMed DOI PMC

Bakker A., Kirwan C. B., Miller M., Stark C. E. L. (2008). Pattern separation in the human hippocampal CA3and dentate gyrus. Science 319, 1640–164210.1126/science.1152882 PubMed DOI PMC

Barch D. M. (2005). The cognitive neuroscience of schizophrenia. Annu. Rev. Clin. Psychol. 1, 321–35310.1146/annurev.clinpsy.1.102803.143959 PubMed DOI

Behrendt R. P. (2010). Contribution of hippocampal region CA3 to consciousness and schizophrenic hallucinations. Neurosci. Biobehav. Rev. 34, 1121–113610.1016/j.neubiorev.2009.12.009 PubMed DOI

Belforte J. E., Zsiros V., Sklar E. R., Jiang Z., Yu G., Li Y., et al. (2010). Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat. Neurosci. 13, 76–8310.1038/nn.2447 PubMed DOI PMC

Benes F. M., Lim B., Matzilevich D., Walsh J. P., Subburaju S., Minns M. (2007). Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars hippocampal GABA alterations in schizophrenia. Proc. Natl. Acad. Sci. U.S.A. 104, 10164–1016910.1073/pnas.0703806104 PubMed DOI PMC

Bowie C. R., Reichenberg A., Patterson T. L., Heaton R. K., Harvey P. D. (2006). Determinants of real-world functional performance in schizophrenia subjects: correlations with cognition, functional capacity, and symptoms. Am. J. Psychiatry 163, 418–42510.1176/appi.ajp.163.3.418 PubMed DOI

Boyer P., Phillips J. L., Rousseau F. L., Ilitvitsky S. (2007). Hippocampal abnormalities and memory deficits: new evidence of a strong pathophysiological link in schizophrenia. Brain Res. Rev. 54, 92–11210.1016/j.brainresrev.2006.12.008 PubMed DOI

Braun I., Genius J., Grunze H., Bender A., Möller H. J., Rujescu D. (2007). Alterations of hippocampal and prefrontal GABAergic interneurons in an animal model of psychosis induced by NMDA receptor antagonism. Schizophr. Res. 97, 254–26310.1016/j.schres.2007.05.005 PubMed DOI

Breier A., Malhotra A. K., Pinals D. A., Weisenfeld N. I., Pickar D. (1997). Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am. J. Psychiatry 154, 805–811 PubMed

Bubeníková-Valešová V., Horacek J., Vrajova M., Höschl C. (2008a). Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci. Biobehav. Rev. 32, 1014–102310.1016/j.neubiorev.2008.03.012 PubMed DOI

Bubeníková-Valešová V., Stuchlík A., Svoboda J., Bureš J., Valeš K. (2008b). Risperidone and ritanserin but not haloperidol block effect of dizocilpine on the active allothetic place avoidance task. Proc. Natl. Acad. Sci. U.S.A. 105, 1061–106610.1073/pnas.0711273105 PubMed DOI PMC

Bureš J., Fenton A. A., Kaminsky Y., Rossier J., Sacchetti B., Zinyuk L. (1997). Dissociation of exteroceptive and idiothetic orientation cues: effect on hippocampal place cells and place navigation. Philos. Trans. R. Soc. Lond. B Biol. Sci. 352, 1515–152410.1098/rstb.1997.0138 PubMed DOI PMC

Buzsáki G., Eidelberg E. (1981). Commissural projection to the dentate gyrus of the rat: evidence for feed-forward inhibition. Brain Res. 230, 346–35010.1016/0006-8993(81)90413-3 PubMed DOI

Christian G. D. (2003). Analytical Chemistry, 6th Edn New York: Wiley

Chrobak J. J., Hinman J. R., Sabolek H. R. (2008). Revealing past memories: proactive interference and ketamine-induced memory deficits. J. Neurosci. 28, 4512–452010.1523/JNEUROSCI.0742-07.2008 PubMed DOI PMC

Cimadevilla J. M., Wesierska M., Fenton A. A., Bureš J. (2001). Inactivating one hippocampus impairs avoidance of a stable room-defined place during dissociation of arena cues from room cues by rotation of the arena. Proc. Natl. Acad. Sci. U.S.A. 98, 3531–353610.1073/pnas.051628398 PubMed DOI PMC

Czerniawski J., Ree F., Chia C., Ramamoorthi K., Kumata Y., Otto T. A. (2011). The importance of having Arc: expression of the immediate-early gene Arc is required for hippocampus-dependent fear conditioning and blocked by NMDA receptor antagonism. J. Neurosci. 31, 11200–1120710.1523/JNEUROSCI.2211-11.2011 PubMed DOI PMC

Danion J. M., Rizzo L., Bruant A. (1999). Functional mechanisms underlying impaired recognition memory and conscious awareness in patients with schizophrenia. Arch. Gen. Psychiatry 56, 639–64410.1001/archpsyc.56.7.639 PubMed DOI

Deutsch S. I., Rosse R. B., Billingslea E. N., Bellack A. S., Mastropaolo J. (2002). Topiramate antagonizes MK-801 in an animal model of schizophrenia. Eur. J. Pharmacol. 449, 121–12510.1016/S0014-2999(02)02041-1 PubMed DOI

Ellenbroek B. A., Cools A. R. (1990). Animal models with construct validity for schizophrenia. Behav. Pharmacol. 1, 469–49010.1097/00008877-199000160-00001 PubMed DOI

Elliott R., McKenna P. J., Robbins T. W., Sahakian B. J. (1998). Specific neuropsychological deficits in schizophrenic patients with preserved intellectual function. Cogn. Neuropsychiatry 3, 45–7010.1080/135468098396242 PubMed DOI

Fenton A. A. (2009). “Neural coordination and psychotic disorganization,” in Information Processing by Neuronal Populations, eds Holscher C., Munk M. H. (London: Cambridge University Press; ), 387–408

Fenton A. A., Bureš J. (1993). Place navigation in rats with unilateral TTX inactivation of the dorsal hippocampus: place but not procedural learning can be lateralised to one hippocampus. Behav. Neurosci. 107, 552–56410.1037/0735-7044.107.4.552 PubMed DOI

Fenton A. A., Kenney J., Kao H.-Y. (2006). Phencyclidine impairs cognition if and only if it co-activates initially independently active neurons. Soc. Biol. Psychiatry 59, 85S

Fenton A. A., Lytton W. W., Barry J. M., Lenck-Santini P. P., Zinyuk L. E., Kubík S., et al. (2010). Attention-like modulation of hippocampus place cell discharge. J. Neurosci. 30, 4613–462510.1523/JNEUROSCI.5576-09.2010 PubMed DOI PMC

Fenton A. A., Wesierska M., Kaminsky Y., Bureš J. (1998). Both here and there: simultaneous expression of autonomous spatial memories in rats. Proc. Natl. Acad. Sci. U.S.A. 95, 11493–1149810.1073/pnas.95.19.11493 PubMed DOI PMC

Gilbert P. E., Kesner R. P., Lee I. (2001). Dissociating hippocampal subregions: double dissociation between dentate gyrus and CA1. Hippocampus 11, 626–63610.1002/hipo.1077 PubMed DOI

Gold J. M., Waltz J. A., Matveeva T. M., Kasanova Z., Strauss G. P., Herbener E. S., et al. (2012). Negative symptoms and the failure to represent the expected reward value of actions: behavioral and computational modeling evidence. Arch. Gen. Psychiatry 69, 129–13810.1001/archgenpsychiatry.2011.1269 PubMed DOI PMC

Green M. F. (1996). What are the functional consequences of neurocognitive deficits in schizophrenia? Am. J. Psychiatry 153, 321–330 PubMed

Green M. F., Kern R. S., Heaton R. K. (2004). Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr. Res. 72, 41–5110.1016/j.schres.2004.09.009 PubMed DOI

Green M. F., Nuechterlein K. H. (1999). Should schizophrenia be treated as a neurocognitive disorder? Schizhopr. Bull. 25, 309–31910.1093/oxfordjournals.schbul.a033380 PubMed DOI

Grunze H. C., Rainnie D. G., Hasselmo M. E., Barkai E., Hearn E. F., McCarley R. W., et al. (1996). NMDA-dependent modulation of CA1 local circuit inhibition. J. Neurosci. 16, 2034–2043 PubMed PMC

Guzowski J. F., Knierim J. J., Moser E. I. (2004). Ensemble dynamics of hippocampal regions CA1 and CA3. Neuron 44, 581–58410.1016/j.neuron.2004.11.003 PubMed DOI

Guzowski J. F., Lyford G. L., Stevenson G. D., Houston F. P., McGaugh J. L., Worley P. F., et al. (2000). Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J. Neurosci. 20, 3993–4001 PubMed PMC

Guzowski J. F., McNaughton B. L., Barnes C. A., Worley P. F. (1999). Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles. Nat. Neurosci. 2, 1120–112410.1038/16046 PubMed DOI

Harrison P. J. (2004). The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology (Berl.) 174, 151–16210.1007/s00213-003-1761-y PubMed DOI

Harvey P. D., Keefe R. S. (2001). Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am. J. Psychiatry 158, 176–18410.1176/appi.ajp.158.2.176 PubMed DOI

Hemsley D. R. (2005). The schizophrenic experience: taken out of context? Schizhopr. Bull. 31, 43–5310.1093/schbul/sbi003 PubMed DOI

Hill S. K., Bishop J. R., Palumbo D., Sweeney J. A. (2010). Effect of second-generation antipsychotics on cognition: current issues and future challenges. Expert Rev. Neurother. 10, 43–5710.1586/ern.09.143 PubMed DOI PMC

Jackson M. E., Homayoun H., Moghaddam B. (2004). NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc. Natl. Acad. Sci. U.S.A. 101, 8467–847210.1073/pnas.0308455101 PubMed DOI PMC

Ježek K., Henriksen E. J., Treves A., Moser E. I., Moser M.-B. (2011). Theta-paced flickering between place-cell maps in the hippocampus. Nature 478, 246–24910.1038/nature10439 PubMed DOI

Keefe R. S. E., Poe M., Walker T. M., Kang J. W., Harvey P. D. (2006). The Schizophrenia Cognition Rating Scale: an interview-based assessment and its relationship to cognition, real-world functioning, and functional capacity. Am. J. Psychiatry 163, 426–43210.1176/appi.ajp.163.3.426 PubMed DOI

Kelemen E., Fenton A. A. (2010). Dynamic grouping of hippocampal neural activity during cognitive control of two spatial frames. PLoS Biol. 8:e1000403.10.1371/journal.pbio.1000403 PubMed DOI PMC

Kelemen E., Fenton A. A. (2013). Key features of human episodic recollection in the cross-episode retrieval of rat hippocampus representations of space. PLoS Biol. 11:e1001607.10.1371/journal.pbio.1001607 PubMed DOI PMC

Kerwin R., Patel S., Meldrum B. (1990). Quantitative autoradiographic analysis of glutamate binding sites in the hippocampal formation in normal and schizophrenic brain post mortem. Neuroscience 39, 25–3210.1016/0306-4522(90)90219-T PubMed DOI

Kobayashi K. (2009). Targeting the hippocampal mossy fiber synapse for the treatment of psychiatric disorders. Mol. Neurobiol. 39, 24–3610.1007/s12035-008-8049-5 PubMed DOI

Kolomeets N. S., Orlovskaya D. D., Rachmanova V. I., Uranova N. A. (2005). Ultrastructural alterations in hippocampal mossy fiber synapses in schizophrenia: a postmortem morphometric study. Synapse 57, 47–5510.1002/syn.20153 PubMed DOI

Kolomeets N. S., Orlovskaya D. D., Uranova N. A. (2007). Decreased numerical density of CA3 hippocampal mossy fiber synapses in schizophrenia. Synapse 61, 615–62110.1002/syn.20405 PubMed DOI

Kubik Š, Fenton A. A. (2005). Behavioral evidence that segregation and representation are dissociable hippocampal functions. J. Neurosci. 25, 9205–921210.1523/JNEUROSCI.1707-05.2005 PubMed DOI PMC

Kubik Š, Miyashita T., Guzowski J. F. (2007). Using immediate-early genes to map hippocampal subregional functions. Learn. Mem. 14, 758–77010.1101/lm.698107 PubMed DOI

Kubik Š, Miyashita T., Kubik-Zahorodna A., Guzowski J. F. (2012). Loss of activity-dependent Arc gene expression in the retrosplenial cortex after hippocampal inactivation: interaction in a higher-order memory circuit. Neurobiol. Learn. Mem. 97, 124–13110.1016/j.nlm.2011.10.004 PubMed DOI

Ledoux A. A., Phillips J. L., Labelle A., Smith A., Bohbot V. D., Boyer P. (2013). Decreased fMRI activity in the hippocampus of patients with schizophrenia compared to healthy control participants, tested on a wayfinding task in a virtual town. Psychiatry Res. 211, 47–5610.1016/j.pscychresns.2012.10.005 PubMed DOI

Lee H., Dvorak D., Kao H.-Y., Duffy A. M., Scharfman H. E., Fenton A. A. (2012). Early cognitive experience prevents adult deficits in a neurodevelopmental schizophrenia model. Neuron 75, 714–72410.1016/j.neuron.2012.06.016 PubMed DOI PMC

Lee I., Yoganarasimha D., Rao G., Knierim J. J. (2004). Comparison of population coherence of place cells in hippocampal subfields CA1 and CA3. Nature 430, 456–45910.1038/nature02739 PubMed DOI

Leutgeb J. K., Leutgeb S., Moser M. B., Moser E. I. (2007). Pattern separation in the dentate gyrus and CA3 of the hippocampus. Science 315, 961–96610.1126/science.1135801 PubMed DOI

Leutgeb S., Leutgeb J. K., Treves A., Moser M.-B., Moser E. I. (2004). Distinct ensemble codes in hippocampal areas CA3 and CA1. Science 305, 1295–129810.1126/science.1100265 PubMed DOI

Lewis D. A., Hashimoto T., Volk D. W. (2005). Cortical inhibitory neurons and schizophrenia. Nat. Rev. Neurosci. 6, 312–32410.1038/nrn1648 PubMed DOI

Li Q., Clark S., Lewis D. V., Wilson W. A. (2002). NMDA receptor antagonists disinhibit rat posterior cingulate and retrosplenial cortices: a potential mechanism of neurotoxicity. J. Neurosci. 22, 3070–3080 PubMed PMC

Link W., Konietzko U., Kauselmann G., Krug M., Schwanke B., Frey U., et al. (1995). Somatodendritic expression of an immediate early gene is regulated by synaptic activity. Proc. Natl. Acad. Sci. U.S.A. 92, 5734–573810.1073/pnas.92.12.5734 PubMed DOI PMC

Lisman J. E., Coyle J. T., Green R. W., Javitt D. C., Benes F. M., Heckers S., et al. (2008). Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci. 31, 234–24210.1016/j.tins.2008.02.005 PubMed DOI PMC

Lobellova V., Entlerova M., Svojanovska B., Hatalova H., Prokopova I., Petrasek T., et al. (2013). Two learning tasks provide evidence for disrupted behavioural flexibility in an animal model of schizophrenia-like behaviour induced by acute MK-801: a dose-response study. Behav. Brain Res. 246, 55–6210.1016/j.bbr.2013.03.006 PubMed DOI

Lyford G. L., Yamagata K., Kaufmann W. E., Barnes C. A., Sanders L. K., Copeland N. G., et al. (1995). Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14, 433–44510.1016/0896-6273(95)90299-6 PubMed DOI

Manschreck T. C., Merrill A. M., Jabbar G., Chun J., Delisi L. E. (2012). Frequency of normative word associations in the speech of individuals at familial high-risk for schizophrenia. Schizophr. Res. 140, 99–10310.1016/j.schres.2012.06.034 PubMed DOI PMC

Martin P., Waters N., Waters S., Carlsson A., Carlsson M. L. (1997). MK-801-induced hyperlocomotion: differential effects of M100907, SDZ PSD 958 and raclopride. Eur. J. Pharmacol. 335, 107–11610.1016/S0014-2999(97)01188-6 PubMed DOI

McHugh T. J., Jones M. W., Quinn J. J., Balthasar N., Coppari R., Elmquist J. K., et al. (2007). Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science 317, 94–9910.1126/science.1140263 PubMed DOI

Miller R. (1989). Hyperactivity of associations in psychosis. Aust. N. Z. J. Psychiatry 23, 241–24810.3109/00048678909062141 PubMed DOI

Mishara A. L., Goldberg T. E. (2004). A meta-analysis and critical review of the effects of conventional neuroleptic treatment on cognition in schizophrenia: opening a closed book. Biol. Psychiatry 55, 1013–102210.1016/j.biopsych.2004.01.027 PubMed DOI

Miyashita T., Kubík Š, Haghighi N., Steward O., Guzowski J. F. (2009). Rapid activation of plasticity-associated gene transcription in hippocampal neurons provides a mechanism for encoding of one-trial experience. J. Neurosci. 29, 898–90610.1523/JNEUROSCI.4588-08.2009 PubMed DOI PMC

Moscovitch M., Nadel L., Winocur G., Gilboa A., Rosenbaum R. S. (2006). The cognitive neuroscience of remote episodic, semantic and spatial memory. Curr. Opin. Neurobiol. 16, 179–19010.1016/j.conb.2006.03.013 PubMed DOI

Moser E. I., Moser M. B. (1998). Distributed encoding and retrieval of spatial memory in the hippocampus. J. Neurosci. 18, 7535–7542 PubMed PMC

Newcomer J. W., Krystal J. H. (2001). NMDA receptor regulation of memory and behavior in humans. Hippocampus 11, 529–54210.1002/hipo.1069 PubMed DOI

Nikiforuk A., Popik P. (2012). Effects of quetiapine and sertindole on subchronic ketamine-induced deficits in attentional set-shifting in rats. Psychopharmacology (Berl.) 220, 65–7410.1007/s00213-011-2487-x PubMed DOI PMC

Nowakowski C., Kaufmann W. A., Adlassnig C., Maier H., Salimi K., Jellinger K. A., et al. (2002). Reduction of chromogranin B-like immunoreactivity in distinct subregions of the hippocampus from individuals with schizophrenia. Schizophr. Res. 58, 43–5310.1016/S0920-9964(01)00389-9 PubMed DOI

Olypher A. V., Klement D., Fenton A. A. (2006). Cognitive disorganization in hippocampus: physiological model of the disorganization in psychosis. J. Neurosci. 26, 158–16810.1523/JNEUROSCI.2064-05.2006 PubMed DOI PMC

Phillips W. A., Silverstein S. M. (2003). Convergence of biological and psychological perspectives on cognitive coordination in schizophrenia. Behav. Brain Sci. 26, 65–8210.1017/S0140525X03000025 PubMed DOI

Plath N., Ohana O., Dammermann B., Errington M. L., Schmitz D., Gross C., et al. (2006). Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Neuron 52, 437–44410.1016/j.neuron.2006.08.024 PubMed DOI

Powel S. B., Geyer M. A. (2007). Overview of animal models of schizophrenia. Curr. Protoc. Neurosci. 39, 9.24.1–9.24.20.10.1002/0471142301.ns0924s39 PubMed DOI

Ragland J. D., Yoon J., Minzenberg M. J., Carter C. S. (2007). Neuroimaging of cognitive disability in schizophrenia: search for a pathophysiological mechanism. Int. Rev. Psychiatry 19, 417–42710.1080/09540260701486365 PubMed DOI PMC

Ranganath C., Minzenberg M. J., Ragland J. D. (2008). The cognitive neuroscience of memory function and dysfunction in schizophrenia. Biol. Psychiatry 64, 18–2510.1016/j.biopsych.2008.04.011 PubMed DOI PMC

Reichenberg A., Caspi A., Harrington H., Houts R., Keefe R. S. E., Murray R. M., et al. (2010). Static and dynamic cognitive deficits in childhood preceding adult schizophrenia: a 30-year study. Am. J. Psychiatry 167, 160–16910.1176/appi.ajp.2009.09040574 PubMed DOI PMC

Romón T., Mengod G., Adell A. (2011). Expression of parvalbumin and glutamic acid decarboxylase-67 after acute administration of MK-801. Implications for the NMDA hypofunction model of schizophrenia. Psychopharmacology (Berl.) 217, 231–23810.1007/s00213-011-2268-6 PubMed DOI

Rorabacher D. B. (1991). Statistical treatment for rejection of deviant values: critical values of Dixon’s “Q” parameter and related subrange ratios at the 95% confidence level. Anal. Chem. 63, 139–14610.1021/ac00002a010 DOI

Rosenheck R., CATIE Study Investigators Group. Leslie D., Keefe R., McEvoy J., Swartz M., et al. (2006). Barriers to employment for people with schizophrenia. Am. J. Psychiatry 163, 411–41710.1176/appi.ajp.163.3.411 PubMed DOI

Rung J. P., Carlsson A., Rydén Markinhuhta K., Carlsson M. L. (2005). (+)-MK-801 induced social withdrawal in rats; a model for negative symptoms of schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 827–83210.1016/j.pnpbp.2005.03.004 PubMed DOI

Schneider F., Gur R. C., Koch K., Backes V., Amunts K., Shah N. J., et al. (2006). Impairment in the specificity of emotion processing in schizophrenia. Am. J. Psychiatry 163, 442–44710.1176/appi.ajp.163.3.442 PubMed DOI

Silverstein S. M., Kovacs I., Corry R., Valone C. (2000). Perceptual organization, the disorganization syndrome, and context processing in chronic schizophrenia. Schizophr. Res. 43, 11–2010.1016/S0920-9964(99)00180-2 PubMed DOI

Sørensen H. J., Mortensen E. L., Schiffman J., Reinisch J. M., Maeda J., Mednick S. A. (2010). Early developmental milestones and risk of schizophrenia: a 45-year follow-up of the Copenhagen Perinatal Cohort. Schizophr. Res. 118, 41–4710.1016/j.schres.2010.01.029 PubMed DOI PMC

Steward O., Worley P. F. (2001). Selective targeting of newly synthesized Arc mRNA to active synapses requires NMDA receptor activation. Neuron 30, 227–24010.1016/S0896-6273(01)00275-6 PubMed DOI

Stuchlík A., Fenton A. A., Bureš J. (2001). Substratal idiothetic navigation of rats is impaired by removal or devaluation of extramaze and intramaze cues. Proc. Natl. Acad. Sci. U.S.A. 98, 3537–354210.1073/pnas.051630498 PubMed DOI PMC

Stuchlík A., Rezácová L., Valeš K., Bubeníková V., Kubík S. (2004). Application of a novel active allothetic place avoidance task (AAPA) in testing a pharmacological model of psychosis in rats: comparison with the Morris Water Maze. Neurosci. Lett. 366, 162–16610.1016/j.neulet.2004.05.037 PubMed DOI

Stuchlík A., Valeš K. (2005). Systemic administration of MK-801, a non-competitive NMDA-receptor antagonist, elicits a behavioural deficit of rats in the active allothetic place avoidance (AAPA) task irrespectively of their intact spatial pretraining. Behav. Brain Res. 159, 163–17110.1016/j.bbr.2004.10.013 PubMed DOI

Tamminga C. A., Southcott S., Sacco C., Wagner A. D., Ghose S. (2012). Glutamate dysfunction in hippocampus: relevance of dentate gyrus and CA3 signaling. Schizophr. Bull. 38, 927–93510.1093/schbul/sbs062 PubMed DOI PMC

Tamminga C. A., Stan A. D., Wagner A. D. (2010). The hippocampal formation in schizophrenia. Am. J. Psychiatry 167, 1178–119310.1176/appi.ajp.2010.09081187 PubMed DOI

Tüscher O., Silbersweig D., Pan H., Smith T., Beutel M., Zonana J., et al. (2005). Processing of environmental sounds in schizophrenic patients: disordered recognition and lack of semantic specificity. Schizophr. Res. 73, 291–29510.1016/j.schres.2004.06.010 PubMed DOI

Uhlhaas P. J., Silverstein S. M., Phillips W. A., Lovell P. G. (2004). Evidence for impaired visual context processing in schizotypy with thought disorder. Schizophr. Res. 68, 249–26010.1016/S0920-9964(03)00184-1 PubMed DOI

Valeš K., Bubeníková-Valešová V., Klement D., Stuchlík A. (2006). Analysis of sensitivity to MK-801 treatment in a novel active allothetic place avoidance task and in the working memory version of the Morris water maze reveals differences between Long-Evans and Wistar rats. Neurosci. Res. 55, 383–38810.1016/j.neures.2006.04.007 PubMed DOI

van der Staay F. J., Rutten K., Erb C., Bloklande A. (2011). Effects of the cognition impairer MK-801 on learning and memory in mice and rats. Behav. Brain Res. 220, 215–22910.1016/j.bbr.2011.01.052 PubMed DOI

Vazdarjanova A., Guzowski J. F. (2004). Differences in hippocampal neuronal population responses to modifications of an environmental context: evidence for distinct, yet complementary, functions of CA3 and CA1 ensembles. J. Neurosci. 24, 6489–649610.1523/JNEUROSCI.0350-04.2004 PubMed DOI PMC

Vazdarjanova A., McNaughton B. L., Barnes C. A., Worley P. F., Guzowski J. F. (2002). Experience-dependent coincident expression of the effector immediate-early genes Arc and Homer 1a in hippocampal and neocortical neuronal networks. J. Neurosci. 22, 10067–10071 PubMed PMC

Vollenweider F. X., Leenders K. L., Scharfetter C., Antonini A., Maguire P., Missimer J., et al. (1997). Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). Eur. Neuropsychopharmacol. 7, 9–2410.1016/S0924-977X(96)00039-9 PubMed DOI

Weinberger D. R. (1999). Cell biology of the hippocampal formation in schizophrenia. Biol. Psychiatry 45, 395–40210.1016/S0006-3223(98)00331-X PubMed DOI

Weiss A. P., Schacter D. L., Goff D. C., Rauch S. L., Alpert N. M., Fischman A. J., et al. (2003). Impaired hippocampal recruitment during normal modulation of memory performance in schizophrenia. Biol. Psychiatry 53, 48–5510.1016/S0006-3223(02)01541-X PubMed DOI

Wentura D., Moritz S., Frings C. (2008). Further evidence for “hyper-priming” in thought-disordered schizophrenic patients using repeated masked category priming. Schizophr. Res. 102, 69–7510.1016/j.schres.2008.04.016 PubMed DOI

Wesierska M., Dockery C., Fenton A. A. (2005). Beyond memory, navigation and inhibition: behavioural evidence for hippocampus-dependent cognitive coordination in the rat. J. Neurosci. 25, 2413–241910.1523/JNEUROSCI.3962-04.2005 PubMed DOI PMC

Westerhausen R., Kompus K., Hugdahl K. (2011). Impaired cognitive inhibition in schizophrenia: a meta-analysis of the Stroop interference effect. Schizophr. Res. 133, 172–18110.1016/j.schres.2011.08.025 PubMed DOI

Yamasaki N., Maekawa M., Kobayashi K., Kajii Y., Maeda J., Soma M., et al. (2008). Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders. Mol. Brain 1, 6.10.1186/1756-6606-1-6 PubMed DOI PMC

Zemanova A., Stankova A., Lobellova V., Svoboda J., Vales K., Vlcek K., et al. (2013). Visuospatial working memory is impaired in an animal model of schizophrenia induced by acute MK-801: an effect of pretraining. Pharmacol. Biochem. Behav. 106, 117–12310.1016/j.pbb.2013.03.014 PubMed DOI

Zinyuk L., Kubík S., Kaminsky Y., Fenton A. A., Bureš J. (2000). Understanding hippocampal activity by using purposeful behavior: place navigation induces place cell discharge in both task-relevant and task irrelevant spatial reference frames. Proc. Natl. Acad. Sci. U.S.A. 97, 3771–377610.1073/pnas.97.7.3771 PubMed DOI PMC

Schizophrenia, the gut microbiota, and new opportunities from optogenetic manipulations of the gut-brain axis

Chronic MK-801 Application in Adolescence and Early Adulthood: A Spatial Working Memory Deficit in Adult Long-Evans Rats But No Changes in the Hippocampal NMDA Receptor Subunits

Acute administration of MK-801 in an animal model of psychosis in rats interferes with cognitively demanding forms of behavioral flexibility on a rotating arena

Cognitive deficits in schizophrenia and other neuropsychiatric disorders: convergence of preclinical and clinical evidence