Gen-Umwelt Interaktionen und Störungen der postnatalen Hirnentwicklung und Neurogenese in Mausmodellen für Schizophrenie
Final Report Abstract
Both genetic and environmental factors, as well as their interaction (GxE), have been proposed as being implicated in the pathophysiology of schizophrenia by disturbing normal brain development. In the present project we investigated the role of components of the glutamate system and of one main environmental risk factor for schizophrenia (perinatal hypoxia) in developmental mouse models of the disease. We identified in pharmacological models of NMDA receptor hypofunction cumulative effects of chronic stress on cortical neurotoxicity, as well as differential roles of the subunits of this receptor in disinhibition of cortical networks. We generated mice with inducible ablation of regular AMPA receptors during late adolescence and characterized schizophrenia-like abnormalities in this model, i.e. hyperlocomotion, sensorimotor gating and working memory deficits. We also analyzed long-term consequences of exposure to chronic perinatal hypoxia and found no behavioral alterations associated with psychiatric disorders. These results suggest a high regenerative capacity of the perinatal brain upon hypoxia and the need of a second genetic susceptibility factor for the protracted development of abnormalities associated with schizophrenia. Altogether these results may contribute to better understanding of the contribution of several genetic and environmental risk factors to the later development of schizophrenia.
Publications
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(2011) Alterations in Postnatal Neurogenesis And Dopamine Dysregulation in Schizophrenia: A Hypothesis. Schizophr Bull 37:674-680
Inta D, Meyer-Lindenberg A, Gass P
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(2012) Combined subunit-specific and unspecific inhibition of NMDA receptors triggers distinct cortical c-fos expression patterns. Synapse 66:752-754
Inta D, Lima-Ojeda JM, Dormann C, Kohr G, Sprengel R, Gass P
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(2012) Sensorimotor gating, working and social memory deficits in mice with reduced expression of the vesicular glutamate transporter VGLUT1. Behav Brain Res, 228:328-332
Inta D, Vogt MA, Perreau-Lenz S, Schneider M, Pfeiffer S, Wojcik SM, Spanagel R, Gass P
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(2013) Pharmacological blockade of GluN2B-containing NMDA receptors induces antidepressant-like effects lacking psychotomimetic action and neurotoxicity in the perinatal and adult rodent brain. Prog Neuropsychopharmacol Biol Psychiatry, 45C:28-33
Lima-Ojeda JM, Vogt MA, Pfeiffer N, Dormann C, Köhr G, Sprengel R, Gass P, Inta D
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(2013) Postweaning social isolation exacerbates neurotoxic effects of the NMDA receptor antagonist MK-801 in rats. J Neural Transm, 120:1605-1609
Inta D, Renz P, Lima-Ojeda JM, Dormann C, Gass P
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(2013). Electroconvulsive therapy induces neurogenesis in frontal rat brain areas. PlosOne, 8:e69869
Inta D, Lima-Ojeda JM, Lau T, Tang W, Sprengel R, Schloss P, Sartorius A, Meyer-Lindenberg A, Gass P
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(2014) Assessment of protracted behavioral abnormalities in two models of intermittent or continuous chronic mild hypoxia in perinatal C57BL/6 mice. Neurosci Lett, 577:77-82
Lima-Ojeda JM, Vogt MA, Richter SH, Dormann C, Schneider M, Gass P, Inta D
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(2014) Phenotype of mice with inducible ablation of GluA1 AMPA receptors during late adolescence: relevance for mental disorders. Hippocampus, 24:424-435
Inta D, Vogt MA, Elkin H, Weber T, Lima-Ojeda JM, Schneider M, Luoni A, Riva MA, Gertz K, Hellmann-Regen J, Kronenberg G, Meyer-Lindenberg A, Sprengel R, Gass P
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(2015) New neurons in the adult striatum: from rodents to humans. Trends Neurosci, 38:517-523
Inta D, Cameron HA, Gass P
