title: Dysequilibrium of neuronal proliferation and apoptosis in a pharmacological animal model of psychosis.
abstract: Growing evidence implicates that abnormal stem cell proliferation and neurodegenerative mechanisms may be involved in the pathogenesis of neuropsychiatric disorders including schizophrenia. Here, we studied the underlying pathomechanisms of psychosis. We are employing a translational approach combining in vivo data with supplementary data from an adult neuronal stem cell-derived cell culture model by generating a large number of analytes in our specimens following a multiplexing strategy. In the animal model the NMDA receptor was chronically antagonized by MK-801 at ultralow doses. As a result of this, we were able to demonstrate a roughly twofold increased density of PCNA positive cells in the germinal zone of the dentate gyrus indicating enhanced neuroproliferative activity. In vitro stem cell experiments additionally pointed to this direction showing an increase both in proliferation and neuronal differentiation after MK-801 treatment. These alterations were partially prevented by coapplication of the dopamine receptor antagonist haloperidol. In addition, apoptotic activity assessed by immunohistochemical demonstration of cleaved caspase-3 stainings was unaffected by MK-801 treatment. These observations were largely supported by microarray gene expression analysis, which permits high-throughput multiplexed assessment of expression data from a comprehensive set of genes and showed parallels with data from human post mortem studies. In conclusion, our data support the notion, that abnormal proliferation due to anti-apoptotic mechanisms may represent a factor in the pathogenesis of psychosis. Thus, research on the exact interplay between glutamatergic neurotransmission and neuronal proliferation deserves more attention. This dual in vivo and in vitro strategy described here may prove as a suitable model for addressing complex neuropsychiatric diseases especially when taking advantage of the potential of multiplex technologies not only in diagnostics but also in basic research.
authors.affiliation: Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Just
authors.initials: J
authors.lastname: Genius
authors.forename: Jens
authors.initials: J
authors.lastname: Benninghoff
authors.forename: Nadine
authors.initials: N
authors.lastname: Reuter
authors.forename: Isabella
authors.initials: I
authors.lastname: Braun
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.forename: Annette
authors.initials: A
authors.lastname: Hartmann
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Möller
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011605:Psychoses, Substance-Induced / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*
chemical_list: D034961:Antigens, Nuclear; D009419:Nerve Tissue Proteins; D018809:Proliferating Cell Nuclear Antigen; C546339:Rbfox3 protein, rat; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D006220:Haloperidol