- Email: [email protected]
PRENATAL IMMUNE ACTIVATION INTERACTSWITH MUTANT DISC1 TO PRODUCE NEURODEVELOPMENTAL AND BEHAVIORAL ALTERATIONS INMICE
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Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279
PRENATAL IMMUNE ACTIVATION INTERACTS WITH MUTANT DISC1 TO PRODUCE NEURODEVELOPMENTAL AND BEHAVIORAL ALTERATIONS IN MICE
Mikhail Pletnikov Johns Hopkins University School of Medicine, Baltimore, Maryland, USA [email protected] The etiology of schizophrenia is likely to have both genetic and environmental components. Recent findings in genetics of schizophrenia, e.g., identification of the Disrupted-In-Schizophrenia (DISC1) gene, have provided a new framework to study gene -infection interactions using in vitro and in vivo approaches. We used our mouse model of inducible expression of mutant DISC1 to evaluate interactions between the mutant protein and prenatal immune activation. Pregnant mice were treated on gestation day 9 with either a synthetic analog of double-stranded RNA, poly IC (5 mg/kg, ip), to mimic intrauterine viral infections during pregnancy, or saline. The neurobehavioral effects of the treatment were assessed in the mutant DISC1 or non-transgenic offspring born and raised by the same dams. The prenatal immune activation led to significant up-regulation of pro-inflammatory cytokines, IL1-â, TNF-α and IL-6, in serum of pregnant mice and brain samples from embryos. Compared to saline-treated mutant DISC1 male mice, poly IC-challenged DISC1 mice exhibited elevated anxiety, decreased exploration of novel social and inanimate objects and depression-like phenotype in forced swim test. The effects of the prenatal immune stimulation on th e volumes of the lateral ventricles, maturation of dendrites and dendritic spines as well as tissue levels of synaptic markers, endogenous DISC1, LIS1, NDEL1 and markers of immune activation are being evaluated and will be presented at the symposium. The proposed approach can help elucidate the specific molecular pathways of gene-environment interplay in the pathogenesis of mental diseases. References [1] Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H, Mori S, Moran TH, Ross CA.Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry. 2008 Feb;13(2):173-86. Epub 2007 Sep 11 PRENATAL INFECTION AND SCHIZOPHRENIA: A FERTILE INTERSECTION BETWEEN EPIDEMIOLOGY AND DEVELOPMENTAL NEUROSCIENCE
John McGrath Queensland Centre for Mental Health Research, Queensland, Australia [email protected] Introduction: Prenatal infection is bad for the developing fetus, and there is robust evidence linking such exposures to adverse adult neuropsychiatric outcomes. But, how far have we come in specifically linking prenatal infection to an increased risk of schizophrenia? Methods: The presentations at the symposium will be integrated with a literature review of clinical research and animal models. Results: Epidemiology has moved from crude ecological analyses to analytic epidemiology based on archived biosamples. Many tantalizing clues have accumulated from this research, but, like so much research exploring the etiology of schizophrenia, the evidence remains fragile. Furthermore, like observational epidemiology in general, the interpretation of these results hangs under the ominous cloud of residual confounding. In contrast, the data emerging from recent experimental research based on animal models of prenatal infection and/or maternal immune activation are robust and informative. This research has prompted us to shift attention away from the specific nature of the infectious agent, to the broader domain of the maternal immune response. The role of the innate immune systems is of particular interest. The animal experiments have allowed us to understand in more precise detail which biological pathways are disrupted by prenatal infection, and how these can subsequently disrupt brain development.
Conclusions: Clues from epidemiology are being actively leveraged in animal research to uncover new mechanisms linking prenatal infection to adverse mental health outcomes. This type of translational epidemiology will be informative for schizophrenia research and for neuroscience in general.
SESSION XVIII
June 24th, 2008
The Two Hit Hypothesis for Pharmacotherapy in the Prodome: Bench to Bedside Evidence BDNF REDUCTIONS IN SCHIZOPHRENIA AND AFFECTIVE DISORDERS MAY BE REVERSIBLE WITH ANTIDEPRESSANT TREATMENT
Cyndi Shannon Weickert 1 , M. Barillo 2 , M.J. Webster 2 1 Schizophrenia Research Institute, University of New South Wales, and Prince of Wales Medical Research Institute, Sydney, NSW, AU; 2 Stanley Medical Research Institute, Gaithersburg MD, USA [email protected] Introduction: BDNF is a key regulator of cortical neuronal maturation and excitatory signaling. We have found a decrease in BDNF and trkB mRNA in the frontal cortex in patients with schizophrenia. The extent to which BDNF and trkB mRNA reductions occur in other cortical areas and in patients suffering from bipolar disorder and major depression is not known. Methods: We used in situ hybridization for BDNF and trkB in cortical areas of the Stanley Consortium brain collection (n=60). We determined if antidepressant medication exposure impacts BDNF mRNA levels in patients suffering from schizophrenia, bipolar disorder or depression. Results: We found that BDNF mRNA was decreased in deep layers of the cingulate cortex in all three forms of ment al illness compared to controls. BDNF and trkB mRNA was also significantly decreased in superficial and deep cortical layers of the temporal cortex in all three groups of patients. We found a significant two-fold increase in BDNF mRNA in multiple cortical regions in those patients who were on antidepressant medication. Conclusions: Neurotrophin transcript reductions are not anatomically restricted to the frontal cortex in the schizophrenic brain, but are found in functionally and anatomic ally distinct cortical regions. Reductions in BDNF and trkB mRNA may be a shared feature of the diagnostically distinct clinical syndromes of bipolar disorder, depression and schizophrenia. We suggest that increased knowledge about the precise natur e of cortical BDNF mRNA reductions in patients with mental illness and of BDNF up-regulation by antidepressant drugs may be used to guide therapeutic strategies. References [1] Weickert CS, Hyde TM, Lipska BK, Herman MM, Weinberger DR, Kleinman JE. Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry. 2003;8:592-610. [2] Hashimoto T, Bergen SE, Nguyen QL, Xu B, Monteggia LM,P ierri JN, Sun Z, Sampson, AR, Lewis DA. Relationship of brain-derived neurotrophic factor and its receptor trkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neruosci. 2005, 25:372-383. ANTI-DEPRESSANTS: AN EFFECTIVE TREATMENT FOR THE PRODROMAL PHASE OF SCHIZOPHRENIA?
B. Cornblatt, C. Smith, A. Auther, L. Baskir, C. Correll Zucker Hillside Hospital, Glen Oaks, New York, USA Introduction: An increasing interest in schizophrenia has been di-
Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279
PRENATAL IMMUNE ACTIVATION INTERACTS WITH MUTANT DISC1 TO PRODUCE NEURODEVELOPMENTAL AND BEHAVIORAL ALTERATIONS IN MICE
Mikhail Pletnikov Johns Hopkins University School of Medicine, Baltimore, Maryland, USA [email protected] The etiology of schizophrenia is likely to have both genetic and environmental components. Recent findings in genetics of schizophrenia, e.g., identification of the Disrupted-In-Schizophrenia (DISC1) gene, have provided a new framework to study gene -infection interactions using in vitro and in vivo approaches. We used our mouse model of inducible expression of mutant DISC1 to evaluate interactions between the mutant protein and prenatal immune activation. Pregnant mice were treated on gestation day 9 with either a synthetic analog of double-stranded RNA, poly IC (5 mg/kg, ip), to mimic intrauterine viral infections during pregnancy, or saline. The neurobehavioral effects of the treatment were assessed in the mutant DISC1 or non-transgenic offspring born and raised by the same dams. The prenatal immune activation led to significant up-regulation of pro-inflammatory cytokines, IL1-â, TNF-α and IL-6, in serum of pregnant mice and brain samples from embryos. Compared to saline-treated mutant DISC1 male mice, poly IC-challenged DISC1 mice exhibited elevated anxiety, decreased exploration of novel social and inanimate objects and depression-like phenotype in forced swim test. The effects of the prenatal immune stimulation on th e volumes of the lateral ventricles, maturation of dendrites and dendritic spines as well as tissue levels of synaptic markers, endogenous DISC1, LIS1, NDEL1 and markers of immune activation are being evaluated and will be presented at the symposium. The proposed approach can help elucidate the specific molecular pathways of gene-environment interplay in the pathogenesis of mental diseases. References [1] Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H, Mori S, Moran TH, Ross CA.Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry. 2008 Feb;13(2):173-86. Epub 2007 Sep 11 PRENATAL INFECTION AND SCHIZOPHRENIA: A FERTILE INTERSECTION BETWEEN EPIDEMIOLOGY AND DEVELOPMENTAL NEUROSCIENCE
John McGrath Queensland Centre for Mental Health Research, Queensland, Australia [email protected] Introduction: Prenatal infection is bad for the developing fetus, and there is robust evidence linking such exposures to adverse adult neuropsychiatric outcomes. But, how far have we come in specifically linking prenatal infection to an increased risk of schizophrenia? Methods: The presentations at the symposium will be integrated with a literature review of clinical research and animal models. Results: Epidemiology has moved from crude ecological analyses to analytic epidemiology based on archived biosamples. Many tantalizing clues have accumulated from this research, but, like so much research exploring the etiology of schizophrenia, the evidence remains fragile. Furthermore, like observational epidemiology in general, the interpretation of these results hangs under the ominous cloud of residual confounding. In contrast, the data emerging from recent experimental research based on animal models of prenatal infection and/or maternal immune activation are robust and informative. This research has prompted us to shift attention away from the specific nature of the infectious agent, to the broader domain of the maternal immune response. The role of the innate immune systems is of particular interest. The animal experiments have allowed us to understand in more precise detail which biological pathways are disrupted by prenatal infection, and how these can subsequently disrupt brain development.
Conclusions: Clues from epidemiology are being actively leveraged in animal research to uncover new mechanisms linking prenatal infection to adverse mental health outcomes. This type of translational epidemiology will be informative for schizophrenia research and for neuroscience in general.
SESSION XVIII
June 24th, 2008
The Two Hit Hypothesis for Pharmacotherapy in the Prodome: Bench to Bedside Evidence BDNF REDUCTIONS IN SCHIZOPHRENIA AND AFFECTIVE DISORDERS MAY BE REVERSIBLE WITH ANTIDEPRESSANT TREATMENT
Cyndi Shannon Weickert 1 , M. Barillo 2 , M.J. Webster 2 1 Schizophrenia Research Institute, University of New South Wales, and Prince of Wales Medical Research Institute, Sydney, NSW, AU; 2 Stanley Medical Research Institute, Gaithersburg MD, USA [email protected] Introduction: BDNF is a key regulator of cortical neuronal maturation and excitatory signaling. We have found a decrease in BDNF and trkB mRNA in the frontal cortex in patients with schizophrenia. The extent to which BDNF and trkB mRNA reductions occur in other cortical areas and in patients suffering from bipolar disorder and major depression is not known. Methods: We used in situ hybridization for BDNF and trkB in cortical areas of the Stanley Consortium brain collection (n=60). We determined if antidepressant medication exposure impacts BDNF mRNA levels in patients suffering from schizophrenia, bipolar disorder or depression. Results: We found that BDNF mRNA was decreased in deep layers of the cingulate cortex in all three forms of ment al illness compared to controls. BDNF and trkB mRNA was also significantly decreased in superficial and deep cortical layers of the temporal cortex in all three groups of patients. We found a significant two-fold increase in BDNF mRNA in multiple cortical regions in those patients who were on antidepressant medication. Conclusions: Neurotrophin transcript reductions are not anatomically restricted to the frontal cortex in the schizophrenic brain, but are found in functionally and anatomic ally distinct cortical regions. Reductions in BDNF and trkB mRNA may be a shared feature of the diagnostically distinct clinical syndromes of bipolar disorder, depression and schizophrenia. We suggest that increased knowledge about the precise natur e of cortical BDNF mRNA reductions in patients with mental illness and of BDNF up-regulation by antidepressant drugs may be used to guide therapeutic strategies. References [1] Weickert CS, Hyde TM, Lipska BK, Herman MM, Weinberger DR, Kleinman JE. Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry. 2003;8:592-610. [2] Hashimoto T, Bergen SE, Nguyen QL, Xu B, Monteggia LM,P ierri JN, Sun Z, Sampson, AR, Lewis DA. Relationship of brain-derived neurotrophic factor and its receptor trkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neruosci. 2005, 25:372-383. ANTI-DEPRESSANTS: AN EFFECTIVE TREATMENT FOR THE PRODROMAL PHASE OF SCHIZOPHRENIA?
B. Cornblatt, C. Smith, A. Auther, L. Baskir, C. Correll Zucker Hillside Hospital, Glen Oaks, New York, USA Introduction: An increasing interest in schizophrenia has been di-