Increased SP4 and SP1 transcription factor expression in the postmortem hippocampus of chronic schizophrenia.

Altered levels of transcription factor specificity protein 4 (SP4) and 1 (SP1) in the cerebellum, prefrontal cortex and/or lymphocytes have been reported in severe psychiatric disorders, including early psychosis, bipolar disorder, and chronic schizophrenia subjects who have undergone long-term antipsychotic treatments. SP4 transgenic mice show altered hippocampal-dependent psychotic-like behaviours and altered development of hippocampal dentate gyrus. Moreover, NMDAR activity regulates SP4 function. The aim of this study was to investigate SP4 and SP1 expression levels in the hippocampus in schizophrenia, and the possible effect of antipsychotics and NMDAR blockade on SP protein levels in rodent hippocampus. We analysed SP4 and SP1 expression levels in the postmortem hippocampus of chronic schizophrenia (n = 14) and control (n = 11) subjects by immunoblot and quantitative RT-PCR. We tested the effect of NMDAR blockade on SP factors in the hippocampus of mouse treated with an acute dose of MK801. We also investigated the effect of subacute treatments with haloperidol and clozapine on SP protein levels in the rat hippocampus. We report that SP4 protein and both SP4 and SP1 mRNA expression levels are significantly increased in the hippocampus in chronic schizophrenia. Likewise, acute treatment with MK801 increased both SP4 and SP1 protein levels in mouse hippocampus. In contrast, subacute treatment with haloperidol and clozapine did not significantly alter SP protein levels in rat hippocampus. These results suggest that SP4 and SP1 upregulation may be part of the mechanisms deregulated downstream of glutamate signalling pathways in schizophrenia and might be contributing to the hippocampal-dependent cognitive deficits of the disorder.

[1]  L. Teruel,et al.  Banco de tejidos neurológicos de Sant Joan de Déu-Serveis de Salut Mental para la investigación de las enfermedades mentales. La importancia de un programa de donación en vida , 2008 .

[2]  Terrence J. Sejnowski,et al.  Prolonged Ketamine Effects in Sp4 Hypomorphic Mice: Mimicking Phenotypes of Schizophrenia , 2013, PloS one.

[3]  J. Kleinman,et al.  Differential effects of haloperidol and clozapine on ionotropic glutamate receptors in rats , 1999, Synapse.

[4]  D. Jeste,et al.  Hippocampal pathologic findings in schizophrenia. A morphometric study. , 1989, Archives of general psychiatry.

[5]  J. Haro,et al.  Reduced expression of SP1 and SP4 transcription factors in peripheral blood mononuclear cells in first-episode psychosis. , 2013, Journal of psychiatric research.

[6]  D. Manahan‐Vaughan,et al.  Long-lasting changes in hippocampal synaptic plasticity and cognition in an animal model of NMDA receptor dysfunction in psychosis , 2013, Neuropharmacology.

[7]  N. Alpert,et al.  Impaired recruitment of the hippocampus during conscious recollection in schizophrenia , 1998, Nature Neuroscience.

[8]  Claus Lindbjerg Andersen,et al.  Normalization of Real-Time Quantitative Reverse Transcription-PCR Data: A Model-Based Variance Estimation Approach to Identify Genes Suited for Normalization, Applied to Bladder and Colon Cancer Data Sets , 2004, Cancer Research.

[9]  H. Holcomb,et al.  Probing the human hippocampus using rCBF: Contrasts in schizophrenia , 2001, Hippocampus.

[10]  Abraham Weizman,et al.  Evidence for the involvement of the hippocampus in the pathophysiology of schizophrenia , 2000, European Neuropsychopharmacology.

[11]  Stephan Heckers,et al.  Impaired hippocampal recruitment during normal modulation of memory performance in schizophrenia , 2003, Biological Psychiatry.

[12]  Shikha Snigdha,et al.  Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism. , 2010, Pharmacology & therapeutics.

[13]  R. Dunn,et al.  Long term antipsychotic treatment does not alter metabolite concentrations in rat striatum: An in vivo magnetic resonance spectroscopy study , 2011, Schizophrenia Research.

[14]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[15]  J. Haro,et al.  Analysis of Sp transcription factors in the postmortem brain of chronic schizophrenia: a pilot study of relationship to negative symptoms. , 2013, Journal of psychiatric research.

[16]  B. Gaudillière,et al.  Transcription factor Sp4 regulates dendritic patterning during cerebellar maturation , 2007, Proceedings of the National Academy of Sciences.

[17]  A. S. Freeman,et al.  Effect of glucose on antipsychotic drug-induced changes in dopamine neuronal activity. , 2001, European journal of pharmacology.

[18]  H. V. Tol,et al.  Schizophrenia: from phenomenology to neurobiology , 2003, Neuroscience & Biobehavioral Reviews.

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

[20]  G. Suske.  The Sp-family of transcription factors. , 1999, Gene.

[21]  Beatriz Paniagua,et al.  Imaging Patients with Psychosis and a Mouse Model Establishes a Spreading Pattern of Hippocampal Dysfunction and Implicates Glutamate as a Driver , 2013, Neuron.

[22]  N. Andreasen,et al.  The Role of the Cerebellum in Schizophrenia , 2008, Biological Psychiatry.

[23]  G. Gill,et al.  Phosphorylation of the transcription factor Sp4 is reduced by NMDA receptor signaling , 2014, Journal of neurochemistry.

[24]  Paul J. Harrison.  The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications , 2004, Psychopharmacology.

[25]  R. Gur,et al.  Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. , 1994, Archives of general psychiatry.

[26]  J. Horáček,et al.  Expression of the Hippocampal NMDA Receptor GluN1 Subunit and Its Splicing Isoforms in Schizophrenia: Postmortem Study , 2010, Neurochemical Research.

[27]  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.

[28]  J. Simpkins,et al.  Glutamate receptor activation evokes calpain‐mediated degradation of Sp3 and Sp4, the prominent Sp‐family transcription factors in neurons , 2007, Journal of neurochemistry.

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

[30]  S. Fatemi,et al.  Levels of phosphodiesterase 4A and 4B are altered by chronic treatment with psychotropic medications in rat frontal cortex , 2010, Synapse.

[31]  Huafu Chen,et al.  Decreased left middle temporal gyrus volume in antipsychotic drug-naive, first-episode schizophrenia patients and their healthy unaffected siblings , 2013, Schizophrenia Research.

[32]  K. Jardemark,et al.  Subchronic treatment with either clozapine, olanzapine or haloperidol produces a hyposensitive response of the rat cortical cells to N-methyl-d-aspartate , 2000, Neuroscience.

[33]  S. Fatemi,et al.  Chronic psychotropic drug treatment causes differential expression of Reelin signaling system in frontal cortex of rats , 2009, Schizophrenia Research.

[34]  S. Fatemi,et al.  The neurodevelopmental hypothesis of schizophrenia, revisited. , 2009, Schizophrenia bulletin.

[35]  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.

[36]  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.

[37]  Karl J. Friston.  Schizophrenia and the disconnection hypothesis , 1999, Acta psychiatrica Scandinavica. Supplementum.

[38]  H. Matsuda,et al.  Regional cerebral blood flow in patients with schizophrenia , 2005, European Archives of Psychiatry and Clinical Neuroscience.

[39]  S. Fatemi,et al.  Chronic psychotropic drug treatment causes differential expression of connexin 43 and GFAP in frontal cortex of rats , 2008, Schizophrenia Research.

[40]  R. Karry,et al.  Sp1 Expression Is Disrupted in Schizophrenia; A Possible Mechanism for the Abnormal Expression of Mitochondrial Complex I Genes, NDUFV1 and NDUFV2 , 2007, PloS one.

[41]  R. Roth,et al.  The Neuropsychopharmacology of Phencyclidine: From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia , 1999, Neuropsychopharmacology.

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

[43]  D. Javitt,et al.  N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: The final common pathway on the road to schizophrenia? , 2010, Brain Research Bulletin.

[44]  E. Bruford,et al.  Mammalian SP/KLF transcription factors: bring in the family. , 2005, Genomics.

[45]  A. Wagner,et al.  The hippocampal formation in schizophrenia. , 2010, The American journal of psychiatry.

[46]  M. Mazurek,et al.  Role of the dopamine transporter in mediating the neuroleptic-induced reduction of tyrosine hydroxylase-immunoreactive midbrain neurons , 2011, Brain Research.

[47]  Shiaoching Gong,et al.  A gene expression atlas of the central nervous system based on bacterial artificial chromosomes , 2003, Nature.

[48]  V. Diwadkar,et al.  Network dysfunction during associative learning in schizophrenia: Increased activation, but decreased connectivity: An fMRI study , 2013, Schizophrenia Research.

[49]  D. Ben-Shachar.  The interplay between mitochondrial complex I, dopamine and Sp1 in schizophrenia , 2009, Journal of Neural Transmission.

[50]  M. LeMay,et al.  Abnormalities of the left temporal lobe and thought disorder in schizophrenia. A quantitative magnetic resonance imaging study. , 1992, The New England journal of medicine.

[51]  D. Grayson,et al.  Induction of the reelin promoter by retinoic acid is mediated by Sp1 , 2007, Journal of neurochemistry.

[52]  J. Dudman,et al.  Antipsychotic drugs elevate mRNA levels of presynaptic proteins in the frontal cortex of the rat , 2005, Biological Psychiatry.

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

[54]  H. Meltzer,et al.  Differential effects of repeated treatment with haloperidol and clozapine on dopamine release and metabolism in the striatum and the nucleus accumbens. , 1991, The Journal of pharmacology and experimental therapeutics.

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

[56]  A. S. Freeman,et al.  Diet and chronic haloperidol effects on rat midbrain dopamine neurons , 2004, Synapse.

[57]  R. Baldessarini,et al.  International consensus study of antipsychotic dosing. , 2010, The American journal of psychiatry.