Molecular and cellular characterization of the APO-SUS/APO-UNSUS rat model displaying schizophrenia-related features
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1
Donders Centre for Neuroscience, NCMLS, Radboud University, Dept. of Molecular Animal Physiology, Netherlands
Schizophrenia is a complex and disabling neuropsychiatric disorder thought to result from a combination of multiple genetic, environmental and epigenetic factors that provide vulnerability to early- and later-life stressors. To address this issue, two rat lines have been pharmacogenetically selected and bred from an outbred Wistar population based on their stereotypical gnawing responses to the dopamine agonist apomorphine. The apomorphine-susceptible (APO-SUS) rats represent a well-characterized animal model displaying schizophrenia-relevant features (high dopaminergic drug sensitivity, decreased prepulse-inhibition, increased exploratory behaviour); apomorphine-unsusceptible (APO-UNSUS) rats are the phenotypic counterparts of the APO-SUS rats. To identify the molecular-(epi) genetic background of the model, we identified single-nucleotide polymorphism (SNP) and mRNA expression differences between the two lines. Using a genome-wide 800K SNP microarray analysis of genomic DNAs from intercrossed APO-SUS/APO-UNSUS rats, we recently discovered that a single genetic variation is linked to the high dopaminergic responsiveness of the APO-SUS rats. To investigate how the interaction of this genetic variation with environmental factors affects gene expression patterns, we performed mRNA expression profiling of the dorsal striatum and prefrontal cortex of APO-SUS and APO-UNSUS rats four hours after an environmental challenge (open field; OF) or a pharmacological challenge (1.5 mg/kg apomorphine injection; APO). A number of gene transcripts differentially expressed in basal and challenged APO-SUS and APO-UNSUS rats were identified, including the immediate early gene transcript fosB, and its alternatively spliced form ∆fosB. We found a higher number of FosB/∆FosB-positive cells in the APO-SUS OF/APO rats compared to that in the APO-SUS control/saline-injected, and also compared to the APO-UNSUS OF, APO and control/saline-injected animals. In addition, we found that the OF and APO challenges caused an overstimulation of only a small subpopulation of specific neuronal cells in the APO-SUS rat brain, and these cells were identified as GABAergic interneurons. It will be of great interest to characterize the functional properties of these cells. Through our studies we hope to contribute to a better understanding of the molecular background for vulnerability to schizophrenia-related features.
Acknowledgements
Support: Top Institute Pharma (Netherlands), grant T5-209
Keywords:
APO-SUS/ UNSUS rat model,
GABAergic interneurons,
Genetic Variation,
mRNA microarray,
Schizophrenia
Conference:
BC11 : Computational Neuroscience & Neurotechnology Bernstein Conference & Neurex Annual Meeting 2011, Freiburg, Germany, 4 Oct - 6 Oct, 2011.
Presentation Type:
Abstract
Topic:
brain disease, network dysfunction and intervention (please use "brain disease, network dysfunction and intervention" as keyword)
Citation:
Meyer
F,
Eijsink
VD,
Van Vugt
RW,
Van Zweeden
M,
Van Hulten
JA,
Verheij
MM,
Valles
A and
Martens
GJ
(2011). Molecular and cellular characterization of the APO-SUS/APO-UNSUS rat model displaying schizophrenia-related features.
Front. Comput. Neurosci.
Conference Abstract:
BC11 : Computational Neuroscience & Neurotechnology Bernstein Conference & Neurex Annual Meeting 2011.
doi: 10.3389/conf.fncom.2011.53.00161
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Received:
22 Aug 2011;
Published Online:
04 Oct 2011.
*
Correspondence:
Dr. Francisca Meyer, Donders Centre for Neuroscience, NCMLS, Radboud University, Dept. of Molecular Animal Physiology, Nijmegen, 6525GA, Netherlands, F.Meyer@ncmls.ru.nl