An-Li Wang1, Benedetta Fazari2, Owen Y Chao3, Susanne Nikolaus4, Svenja V Trossbach5, Carsten Korth6, Fernando J Sialana7, Gert Lubec8, Joseph P Huston9, Claudia Mattern10, Maria Angelica de Souza Silva11. 1. Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich Heine University Düsseldorf, Germany. Electronic address: An-Li.Wang@uni-duesseldorf.de. 2. Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich Heine University Düsseldorf, Germany. Electronic address: Benedetta.Fazari@uni-duesseldorf.de. 3. Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich Heine University Düsseldorf, Germany; Department of Biomedical Sciences, School of Medicine, University of Minnesota, USA. Electronic address: owenchao@gmail.com. 4. Clinic of Nuclear Medicine, University Hospital Düsseldorf, Düsseldorf, Germany. Electronic address: susanne.nikolaus@uni-duesseldorf.de. 5. Department Neuropathology, Medical Faculty, Heinrich Heine University Düsseldorf, Germany. Electronic address: svenja.trossbach@hhu.de. 6. Department Neuropathology, Medical Faculty, Heinrich Heine University Düsseldorf, Germany. Electronic address: ckorth@uni-duesseldorf.de. 7. Department of Pharmaceutical Chemistry, University of Vienna, 1090, Austria. Electronic address: fsialana@yahoo.com. 8. Department of Pharmaceutical Chemistry, University of Vienna, 1090, Austria. Electronic address: gert.lubec@lubeclab.com. 9. Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich Heine University Düsseldorf, Germany. Electronic address: jph@uni-duesseldorf.de. 10. M et P Pharma AG, 6376 Emmetten, Switzerland; Oceanographic Center, Nova Southeastern University, Fort Lauderdale, FL 33314, USA. Electronic address: cu.mattern@bluewin.ch. 11. Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich Heine University Düsseldorf, Germany. Electronic address: desouza@uni-duesseldorf.de.
Abstract
The Disrupted-in-Schizophrenia 1 (DISC1) gene has been associated with mental illnesses such as major depression and schizophrenia. The transgenic DISC1 (tgDISC1) rat, which overexpresses the human DISC1 gene, is known to exhibit deficient dopamine (DA) homeostasis. To ascertain whether the DISC1 gene also impacts cognitive functions, 14-15 months old male tgDISC1 rats and wild-type controls were subjected to the novel object preference (NOP) test and the object-based attention test (OBAT) in order to assess short-term memory (1 h), long-term memory (24 h), and attention. RESULTS: The tgDISC1 group exhibited intact short-term memory, but deficient long-term-memory in the NOP test and deficient attention-related behavior in the OBAT. In a different group of tgDISC1 rats, 3 mg/kg intranasally applied dopamine (IN-DA) or its vehicle was applied prior to the NOP or the OBAT test. IN-DA reversed cognitive deficits in both the NOP and OBAT tests. In a further cohort of tgDISC1 rats, post-mortem levels of DA, noradrenaline, serotonin and acetylcholine were determined in a variety of brain regions. The tgDISC1 group had less DA in the neostriatum, hippocampus and amygdala, less acetylcholine in neostriatum, nucleus accumbens, hippocampus, and amygdala, more serotonin in the nucleus accumbens, and less serotonin and noradrenaline in the amygdala. CONCLUSIONS: Our findings show that DISC1 overexpression and misassembly is associated with deficits in long-term memory and attention-related behavior. Since behavioral impairments in tgDISC1 rats were reversed by IN-DA, DA deficiency may be a major cause for the behavioral deficits expressed in this model.
The Disrupted-in-Schizophrenia 1 (DISC1) gene has been associated with mental illnesses such as major depression and schizophrenia. The transgenic DISC1 (tgDISC1) rat, which overexpresses the humanDISC1 gene, is known to exhibit deficient dopamine (DA) homeostasis. To ascertain whether the DISC1 gene also impacts cognitive functions, 14-15 months old male tgDISC1 rats and wild-type controls were subjected to the novel object preference (NOP) test and the object-based attention test (OBAT) in order to assess short-term memory (1 h), long-term memory (24 h), and attention. RESULTS: The tgDISC1 group exhibited intact short-term memory, but deficient long-term-memory in the NOP test and deficient attention-related behavior in the OBAT. In a different group of tgDISC1 rats, 3 mg/kg intranasally applied dopamine (IN-DA) or its vehicle was applied prior to the NOP or the OBAT test. IN-DA reversed cognitive deficits in both the NOP and OBAT tests. In a further cohort of tgDISC1 rats, post-mortem levels of DA, noradrenaline, serotonin and acetylcholine were determined in a variety of brain regions. The tgDISC1 group had less DA in the neostriatum, hippocampus and amygdala, less acetylcholine in neostriatum, nucleus accumbens, hippocampus, and amygdala, more serotonin in the nucleus accumbens, and less serotonin and noradrenaline in the amygdala. CONCLUSIONS: Our findings show that DISC1 overexpression and misassembly is associated with deficits in long-term memory and attention-related behavior. Since behavioral impairments in tgDISC1 rats were reversed by IN-DA, DAdeficiency may be a major cause for the behavioral deficits expressed in this model.
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