Translational Neuroscience of Schizophrenia: Seeking a Meeting of Minds Between Mouse and Man

Department of Neuroscience and Pharmacology, University Medical Center Utrecht, 3584CG Utrecht, The Netherlands.
Science translational medicine (Impact Factor: 15.84). 09/2011; 3(102):102mr3. DOI: 10.1126/scitranslmed.3002917
Source: PubMed


Understanding the etiology of developmental brain disorders such as schizophrenia is critical for achieving advances in treatment and requires new research strategies that control for individual variation in genetic background, environmental challenges, and expression of phenotype. SYSGENET, a European systems genetics network for the study of complex genetic human diseases with mouse genetic reference populations, brought together in Helsinki a cross-disciplinary group of clinical and basic scientists and mouse geneticists to debate, formulate, and prioritize a strategy for future research based on mouse models. The main conclusions of this meeting are summarized here.

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Available from: Martien J Kas,
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    • "An ethological approach to identifying and assessing these basic behavioural building blocks is beginning to bear fruit (Gould and Gottesman 2006; Kas et al. 2007, 2011a). For example in modelling schizophrenia, anhedonia, asociality and avolition are at least theoretically accessible through behavioural assays in both humans and animals (Kas et al. 2011a) and characteristics of autistic spectrum disorders, for example insistence on routine and resistance to change in tasks that involve reversal learning or set shifting, high anxiety and low socialization can be all assessed in mouse models (Bishop and Lahvis 2011; Amodeo et al. 2012; Moy et al. 2007; Naviaux et al. 2014; Nestler and Hyman 2010). "
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    • "With the identification of genetic and novel epigenetic mechanisms that determine behavioral outcome, new light has shed on the complexity of brain disorders. Unraveling this complexity will require large disease populations to identify genetic factors with small effect sizes and/or systematic studies in animals that allow the control of both genetic and environmental conditions (Kas et al., 2011; Schughart et al., 2012). The availability of genetically modified rodents and genetic reference populations have provided complementary tools to study the role of genetic factors in behavioral phenotypes. "
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    • "In this context, studies using animal models can contribute considerably to the understanding of the development of psychiatric disorders as they allow systematic studies of phenotype expression in a controlled genetic background and environment (Kalueff et al., 2008; Kas et al., 2011; Tecott and Nestler, 2004). Most studies using these models predominantly focus on adult ages and surpass earlier windows of development that may already be affected. "
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    ABSTRACT: The behavioral characterization of animal models of psychiatric disorders is often based upon independent traits measured at adult age. To model the neurodevelopmental aspects of psychiatric pathogenesis, we introduce a novel approach for a developmental behavioral analysis in mice. C57BL/6 J (C57) mice were used as a reference strain and compared with 129S1/SvImJ (129 Sv), BTBR T+tf/J (BTBR) and A/J (AJ) strains as marker strains for aberrant development. Mice were assessed at pre-adolescence (4 weeks), adolescence (6 weeks), early adulthood (8 weeks) and in adulthood (10–12 weeks) on a series of behavioral tasks measuring general health, neurological reflexes, locomotor activity, anxiety, short- and long term memory and cognitive flexibility. Developmental delays in short-term object memory were associated with either a hypo-reactive profile in 129 Sv mice or a hyper-reactive profile in BTBR mice. Furthermore, BTBR mice showed persistent high levels of repetitive grooming behavior during all developmental stages that was associated with the adult expression of cognitive rigidity. In addition, strain differences in development were observed in puberty onset, touch escape, and body position. These data showed that this longitudinal testing battery provides sufficient behavioral and cognitive resolution during different development stages and offers the opportunity to address the behavioral developmental trajectory in genetic mouse models for neurodevelopmental disorders. Furthermore, the data revealed that the assessment of multiple behavioral and cognitive domains at different developmental stages is critical to determine confounding factors (e.g., impaired motor behavior) that may interfere with the behavioral testing performance in mouse models for brain disorders.
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