Prolonged Ketamine Effects in Sp4 Hypomorphic Mice: Mimicking Phenotypes of Schizophrenia

It has been well established that schizophrenia patients display impaired NMDA receptor (NMDAR) functions as well as exacerbation of symptoms in response to NMDAR antagonists. Abnormal NMDAR signaling presumably contributes to cognitive deficits which substantially contribute to functional disability in schizophrenia. Establishing a mouse genetic model will help investigate molecular mechanisms of hypoglutmatergic neurotransmission in schizophrenia. Here, we examined the responses of Sp4 hypomorphic mice to NMDAR antagonists in electroencephalography and various behavioral paradigms. Sp4 hypomorphic mice, previously reported to have reduced NMDAR1 expression and LTP deficit in hippocampal CA1, displayed increased sensitivity and prolonged responses to NMDAR antagonists. Molecular studies demonstrated reduced expression of glutamic acid decarboxylase 67 (GAD67) in both cortex and hippocampus, consistent with abnormal gamma oscillations in Sp4 hypomorphic mice. On the other hand, human SP4 gene was reported to be deleted in schizophrenia. Several human genetic studies suggested the association of SP4 gene with schizophrenia and other psychiatric disorders. Therefore, elucidation of the Sp4 molecular pathway in Sp4 hypomorphic mice may provide novel insights to our understanding of abnormal NMDAR signaling in schizophrenia.

[1]  M. Alegre,et al.  Ketamine-Induced Oscillations in the Motor Circuit of the Rat Basal Ganglia , 2011, PloS one.

[2]  R. Conley,et al.  Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia. , 2000, The American journal of psychiatry.

[3]  A. Sampson,et al.  Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features. , 2011, The American journal of psychiatry.

[4]  M. Goodell,et al.  Genome-wide association study of recurrent early-onset major depressive disorder , 2010, Molecular Psychiatry.

[5]  J. Kelsoe,et al.  Impaired postnatal development of hippocampal dentate gyrus in Sp4 null mutant mice , 2007, Genes, brain, and behavior.

[6]  M. Geyer,et al.  Four factors underlying mouse behavior in an open field , 2012, Behavioural Brain Research.

[7]  J. Kelsoe,et al.  Transcription Factor SP4 Is a Susceptibility Gene for Bipolar Disorder , 2009, PloS one.

[8]  D. Clair,et al.  Association within a family of a balanced autosomal translocation with major mental illness , 1990, The Lancet.

[9]  A. Sampson,et al.  Gene Expression Deficits in a Subclass of GABA Neurons in the Prefrontal Cortex of Subjects with Schizophrenia , 2003, The Journal of Neuroscience.

[10]  K. Nakazawa,et al.  Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes , 2010, Nature Neuroscience.

[11]  A. Sampson,et al.  Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. , 2000, Archives of general psychiatry.

[12]  D. Javitt,et al.  Recent advances in the phencyclidine model of schizophrenia. , 1991, The American journal of psychiatry.

[13]  D. Supp,et al.  Sp4, a member of the Sp1-family of zinc finger transcription factors, is required for normal murine growth, viability, and male fertility. , 1996, Developmental biology.

[14]  Martin S. Taylor,et al.  Disruption of two novel genes by a translocation co-segregating with schizophrenia. , 2000, Human molecular genetics.

[15]  M A Geyer,et al.  Disruption of prepulse inhibition and increases in locomotor activity by competitive N-methyl-D-aspartate receptor antagonists in rats. , 1999, The Journal of pharmacology and experimental therapeutics.

[16]  H. Holcomb,et al.  Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia , 2005, Neuropsychopharmacology.

[17]  Paul J Carlson,et al.  A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. , 2006, Archives of general psychiatry.

[18]  Richard Redon,et al.  Confirmed rare copy number variants implicate novel genes in schizophrenia. , 2010, Biochemical Society transactions.

[19]  S. Kapur,et al.  NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2 receptors—implications for models of schizophrenia , 2002, Molecular Psychiatry.

[20]  W. Singer,et al.  Progress in Biophysics and Molecular Biology , 1965 .

[21]  B. Moghaddam,et al.  NMDA Receptor Hypofunction Produces Opposite Effects on Prefrontal Cortex Interneurons and Pyramidal Neurons , 2007, The Journal of Neuroscience.

[22]  David A Lewis,et al.  Glutamate Receptor Subtypes Mediating Synaptic Activation of Prefrontal Cortex Neurons: Relevance for Schizophrenia , 2011, The Journal of Neuroscience.

[23]  S. Nakanishi,et al.  Molecular cloning and characterization of the rat NMDA receptor , 1991, Nature.

[24]  Carol A. Tamminga,et al.  Subanesthetic Doses of Ketamine Stimulate Psychosis in Schizophrenia , 1995, Neuropsychopharmacology.

[25]  B. Moghaddam,et al.  Corticolimbic Dopamine Neurotransmission Is Temporally Dissociated from the Cognitive and Locomotor Effects of Phencyclidine , 1998, The Journal of Neuroscience.

[26]  G. Rosenbaum,et al.  Study of a new schizophrenomimetic drug; sernyl. , 1959, A.M.A. archives of neurology and psychiatry.

[27]  P. Schofield,et al.  Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia , 2012, Molecular Psychiatry.

[28]  M. Geyer,et al.  Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization , 2005, Molecular Psychiatry.

[29]  J. Krystal,et al.  Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. , 1994, Archives of general psychiatry.

[30]  Bita Moghaddam,et al.  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 , 1997, The Journal of Neuroscience.

[31]  F. Razoux,et al.  Ketamine, at a Dose that Disrupts Motor Behavior and Latent Inhibition, Enhances Prefrontal Cortex Synaptic Efficacy and Glutamate Release in the Nucleus Accumbens , 2007, Neuropsychopharmacology.

[32]  J. Deakin,et al.  Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses , 2001, Neuroreport.

[33]  L. H. Finkel,et al.  N-methyl-d-aspartic acid receptor antagonist–induced frequency oscillations in mice recreate pattern of electrophysiological deficits in schizophrenia , 2009, Neuroscience.

[34]  Xianjin Zhou,et al.  System-Wide Immunohistochemical Analysis of Protein Co-Localization , 2012, PloS one.

[35]  D. McCormick,et al.  Ionic Mechanisms Underlying Repetitive High-Frequency Burst Firing in Supragranular Cortical Neurons , 2000, The Journal of Neuroscience.

[36]  Marc G Caron,et al.  Mice with Reduced NMDA Receptor Expression Display Behaviors Related to Schizophrenia , 1999, Cell.

[37]  Jessica A. Cardin,et al.  A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior , 2011, Molecular Psychiatry.

[38]  Hee-Sup Shin,et al.  Mutant Mice and Neuroscience: Recommendations Concerning Genetic Background , 1997, Neuron.

[39]  Jessica A. Cardin,et al.  Driving fast-spiking cells induces gamma rhythm and controls sensory responses , 2009, Nature.

[40]  J. Potash,et al.  Novel loci for major depression identified by genome-wide association study of STAR*D and meta-analysis of three studies , 2009, Molecular Psychiatry.

[41]  D J Porteous,et al.  Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. , 2001, American journal of human genetics.

[42]  Anil K Malhotra,et al.  Ketamine-Induced Exacerbation of Psychotic Symptoms and Cognitive Impairment in Neuroleptic-Free Schizophrenics , 1997, Neuropsychopharmacology.

[43]  Mark Jeremy Hunt,et al.  Ketamine Dose-Dependently Induces High-Frequency Oscillations in the Nucleus Accumbens in Freely Moving Rats , 2006, Biological Psychiatry.

[44]  Dheeraj Malhotra,et al.  Reduced NMDAR1 expression in the Sp4 hypomorphic mouse may contribute to endophenotypes of human psychiatric disorders. , 2010, Human molecular genetics.

[45]  M. Low,et al.  Differential Contributions of Dopamine D1, D2, and D3 Receptors to MDMA-Induced Effects on Locomotor Behavior Patterns in Mice , 2006, Neuropsychopharmacology.

[46]  Michael F. Green,et al.  Analysis of 94 candidate genes and 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia. , 2011, The American journal of psychiatry.

[47]  Xiaoyu Peng,et al.  Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies , 2008, The Lancet Neurology.

[48]  Igor Jurisica,et al.  CpG Island microarray probe sequences derived from a physical library are representative of CpG Islands annotated on the human genome , 2005, Nucleic acids research.

[49]  M. Geyer,et al.  Lamotrigine prevents ketamine but not amphetamine-induced deficits in prepulse inhibition in mice , 2003, Psychopharmacology.

[50]  J. Haro,et al.  The transcription factor SP4 is reduced in postmortem cerebellum of bipolar disorder subjects: control by depolarization and lithium , 2011, Bipolar disorders.