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Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes

Abstract

Cortical GABAergic dysfunction may underlie the pathophysiology of psychiatric disorders, including schizophrenia. Here, we characterized a mouse strain in which the essential NR1 subunit of the NMDA receptor (NMDAR) was selectively eliminated in 40–50% of cortical and hippocampal interneurons in early postnatal development. Consistent with the NMDAR hypofunction theory of schizophrenia, distinct schizophrenia-related symptoms emerged after adolescence, including novelty-induced hyperlocomotion, mating and nest-building deficits, as well as anhedonia-like and anxiety-like behaviors. Many of these behaviors were exacerbated by social isolation stress. Social memory, spatial working memory and prepulse inhibition were also impaired. Reduced expression of glutamic acid decarboxylase 67 and parvalbumin was accompanied by disinhibition of cortical excitatory neurons and reduced neuronal synchrony. Postadolescent deletion of NR1 did not result in such abnormalities. These findings suggest that early postnatal inhibition of NMDAR activity in corticolimbic GABAergic interneurons contributes to the pathophysiology of schizophrenia-related disorders.

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Figure 1: Generation of a corticolimbic GABAergic neuron-restricted Cre line.
Figure 2: Restricted NR1 deletion in GABAergic neurons in cortex and hippocampus.
Figure 3: Early postnatal NR1 deletion leads to schizophrenia-related behaviors.
Figure 4: Decreased expression of GAD67 and parvalbumin in NR1-deleted neurons.
Figure 5: Increased firing of cortical excitatory neurons accompanied by reduced neuronal synchrony.
Figure 6: No schizophrenia-related phenotypes were observed following adult NR1 deletion.
Figure 7: Adult NR1 deletion did not alter firing rate or synchronous firing of cortical excitatory neurons.

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References

  1. Lodge, D. & Anis, N.A. Effects of phencyclidine on excitatory amino acid activation of spinal interneurones in the cat. Eur. J. Pharmacol. 77, 203–204 (1982).

    Article  CAS  PubMed  Google Scholar 

  2. Javitt, D.C. Negative schizophrenic symptomatology and the PCP (phencyclidine) model of schizophrenia. Hillside J. Clin. Psychiatry 9, 12–35 (1987).

    CAS  PubMed  Google Scholar 

  3. Olney, J.W. in Excitatory Acid Acids in Health and Disease (ed. D. Lodge) 337–351 (Wiley, London, 1988).

  4. Deutsch, S.I., Mastropaolo, J., Schwartz, B.L., Rosse, R.B. & Morihisa, J.M.A. “glutamatergic hypothesis” of schizophrenia. Rationale for pharmacotherapy with glycine. Clin. Neuropharmacol. 12, 1–13 (1989).

    Article  CAS  PubMed  Google Scholar 

  5. Krystal, J.H. et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch. Gen. Psychiatry 51, 199–214 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Coyle, J.T. The glutamatergic dysfunction hypothesis for schizophrenia. Harv. Rev. Psychiatry 3, 241–253 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Lahti, A.C., Koffel, B., LaPorte, D. & Tamminga, C.A. Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 13, 9–19 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Gainetdinov, R.R., Mohn, A.R. & Caron, M.G. Genetic animal models: focus on schizophrenia. Trends Neurosci. 24, 527–533 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Labrie, V., Lipina, T. & Roder, J.C. Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia. Psychopharmacology (Berl.) 200, 217–230 (2008).

    Article  CAS  Google Scholar 

  10. Benes, F.M. & Berretta, S. GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 25, 1–27 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Lewis, D.A., Hashimoto, T. & Volk, D.W. Cortical inhibitory neurons and schizophrenia. Nat. Rev. Neurosci. 6, 312–324 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Akbarian, S. & Huang, H.S. Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders. Brain Res. Rev. 52, 293–304 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Eyles, D.W., McGrath, J.J. & Reynolds, G.P. Neuronal calcium-binding proteins and schizophrenia. Schizophr. Res. 57, 27–34 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Olney, J.W. & Farber, N.B. Glutamate receptor dysfunction and schizophrenia. Arch. Gen. Psychiatry 52, 998–1007 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Grunze, H.C. et al. NMDA-dependent modulation of CA1 local circuit inhibition. J. Neurosci. 16, 2034–2043 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jackson, M.E., Homayoun, H. & Moghaddam, B. NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc. Natl. Acad. Sci. USA 101, 8467–8472 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hasegawa, M. et al. MK-801 increases endogenous acetylcholine release in the rat parietal cortex: a study using brain microdialysis. Neurosci. Lett. 150, 53–56 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Moghaddam, B., Adams, B., Verma, A. & Daly, D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J. Neurosci. 17, 2921–2927 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Vollenweider, F.X. et al. Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). Eur. Neuropsychopharmacol. 7, 9–24 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cochran, S.M. et al. Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs. Neuropsychopharmacology 28, 265–275 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Keilhoff, G., Becker, A., Grecksch, G., Wolf, G. & Bernstein, H.G. 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 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Rujescu, D. et al. A pharmacological model for psychosis based on N-methyl-d-aspartate receptor hypofunction: molecular, cellular, functional and behavioral abnormalities. Biol. Psychiatry 59, 721–729 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Behrens, M.M. et al. Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science 318, 1645–1647 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Morrow, B.A., Elsworth, J.D. & Roth, R.H. Repeated phencyclidine in monkeys results in loss of parvalbumin-containing axo-axonic projections in the prefrontal cortex. Psychopharmacology (Berl.) 192, 283–290 (2007).

    Article  CAS  Google Scholar 

  27. Dang, M.T. et al. Disrupted motor learning and long-term synaptic plasticity in mice lacking NMDAR1 in the striatum. Proc. Natl. Acad. Sci. USA 103, 15254–15259 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Piskulic, D., Olver, J.S., Norman, T.R. & Maruff, P. Behavioral studies of spatial working memory dysfunction in schizophrenia: a quantitative literature review. Psychiatry Res. 150, 111–121 (2007).

    Article  PubMed  Google Scholar 

  29. Braff, D.L., Geyer, M.A. & Swerdlow, N.R. Human studies of prepulse inhibition of startle: normal subjects, patient groups and pharmacological studies. Psychopharmacology (Berl.) 156, 234–258 (2001).

    Article  CAS  Google Scholar 

  30. Bubeníková-Valesová, V., Horácek, J., Vrajová, M. & Höschl, C. Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci. Biobehav. Rev. 32, 1014–1023 (2008).

    Article  PubMed  Google Scholar 

  31. Tsien, J.Z., Huerta, P.T. & Tonegawa, S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87, 1327–1338 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Whitfield-Gabrieli, S. et al. Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proc. Natl. Acad. Sci. USA 106, 1279–1284 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cannon, M. et al. Premorbid social functioning in schizophrenia and bipolar disorder: similarities and differences. Am. J. Psychiatry 154, 1544–1550 (1997).

    CAS  PubMed  Google Scholar 

  34. Agid, O., Kohn, Y. & Lerer, B. Environmental stress and psychiatric illness. Biomed. Pharmacother. 54, 135–141 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Lim, E.P., Verma, V., Nagarajah, R. & Dawe, G.S. Propranolol blocks chronic risperidone treatment-induced enhancement of spatial working memory performance of rats in a delayed matching-to-place water maze task. Psychopharmacology (Berl.) 191, 297–310 (2007).

    Article  CAS  Google Scholar 

  36. Houthoofd, S.A., Morrens, M. & Sabbe, B.G. Cognitive and psychomotor effects of risperidone in schizophrenia and schizoaffective disorder. Clin. Ther. 30, 1565–1589 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Reilly, J.L., Harris, M.S., Keshavan, M.S. & Sweeney, J.A. Adverse effects of risperidone on spatial working memory in first-episode schizophrenia. Arch. Gen. Psychiatry 63, 1189–1197 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Carter, C.J. Schizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability. Schizophr. Res. 86, 1–14 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Martucci, L. et al. N-methyl-d-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia: TDT and case-control analyses. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 119B, 24–27 (2003).

    Article  PubMed  Google Scholar 

  40. Huang, Z.J. Activity-dependent development of inhibitory synapses and innervation pattern: role of GABA signalling and beyond. J. Physiol. (Lond.) 587, 1881–1888 (2009).

    Article  CAS  Google Scholar 

  41. Weinberger, D.R. Implications of normal brain development for the pathogenesis of schizophrenia. Arch. Gen. Psychiatry 44, 660–669 (1987).

    Article  CAS  PubMed  Google Scholar 

  42. Hagberg, H., Ichord, R., Palmer, C., Yager, J.Y. & Vannucci, S.J. Animal models of developmental brain injury: relevance to human disease. A summary of the panel discussion from the Third Hershey Conference on Developmental Cerebral Blood Flow and Metabolism. Dev. Neurosci. 24, 364–366 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Gong, S., Yang, X.W., Li, C. & Heintz, N. Highly efficient modification of bacterial artificial chromosomes (BACs) using novel shuttle vectors containing the R6Kgamma origin of replication. Genome Res. 12, 1992–1998 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Brautigan, D.L., Sunwoo, J., Labbe, J.C., Fernandez, A. & Lamb, N.J. Cell cycle oscillation of phosphatase inhibitor-2 in rat fibroblasts coincident with p34cdc2 restriction. Nature 344, 74–78 (1990).

    Article  CAS  PubMed  Google Scholar 

  45. Jinde, S. et al. Lack of kainic acid-induced gamma oscillations predicts subsequent CA1 excitotoxic cell death. Eur. J. Neurosci. 30, 1036–1055 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Cobos, I. et al. Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy. Nat. Neurosci. 8, 1059–1068 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Weisstaub, N.V. et al. Cortical 5–HT2A receptor signaling modulates anxiety-like behaviors in mice. Science 313, 536–540 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Ferguson, J.N. et al. Social amnesia in mice lacking the oxytocin gene. Nat. Genet. 25, 284–288 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Ikegaya, Y., Nishiyama, N. & Matsuki, N. L-type Ca2+ channel blocker inhibits mossy fiber sprouting and cognitive deficits following pilocarpine seizures in immature mice. Neuroscience 98, 647–659 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Paylor, R. & Crawley, J.N. Inbred strain differences in prepulse inhibition of the mouse startle response. Psychopharmacology (Berl.) 132, 169–180 (1997).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank N. Heintz for pLD53.SCAEB plasmid and the BAC homologous recombination protocol, F. Costantini for the loxP-flanked Rosa26-EYFP mouse strain, D.L. Brautigan for antibody to Ppp1r2, B. Condie and J. Rubenstein for Gad67 cDNA, J. Pickel for oocyte injections, J.N. Crawley for advice on behavioral testing, S. Zhang, J. Okolonta and M. Taylor for technical and animal care assistance, H. Matsunami for in situ hybridization protocol, Y. Kubota for immunostaining protocol and J. Yamamoto for Neuralynx/Xclust2 conversion software. We thank D.R. Weinberger, M.M. Behrens, G. Kunos, I. Henter, K.M. Christian, H. Giesen and H.A. Nash for critical comments on the manuscript. We also acknowledge the CURE/Digestive diseases research center at the University of California Los Angeles and the US National Institute of Mental Health Chemical Synthesis and Drug Supply Program for antibodies and risperidone, respectively. This work was supported by the Intramural Research Program of the US National Institute of Mental Health and of the US National Institute on Alcohol Abuse and Addiction.

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J.E.B. and K.N. designed most of the experiments and wrote the paper. V.Z. was responsible for the slice physiology data. E.R.S. and Z.J. conducted some of the behavioral testing. G.Y. and E.M.Q. were responsible for the visually evoked potentials. Y.L. provided animal resources. All other experiments were data-collected by J.E.B. All authors discussed the results and commented on the manuscript.

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Correspondence to Kazu Nakazawa.

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Belforte, J., Zsiros, V., Sklar, E. et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci 13, 76–83 (2010). https://doi.org/10.1038/nn.2447

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