Introduction
The last decade has seen the mouse become one of the model species of choice for researchers studying brain function and neuropsychiatric diseases. This trend has been catalyzed by two key scientific advances during this period: the emergence of techniques for precisely manipulating the mouse genome, such as gene-targeting (Capecchi, 2005), and the sequencing of the human genome (International Human Genome Sequencing Consortium, 2004). In addition, the mouse lends itself to the application of other techniques, both traditional (e.g., drug treatments, brain lesions) and cutting-edge (e.g., RNA interference, opticogenetics), for manipulating molecules, neurotransmitters and circuits in the brain. As such, the mouse-based laboratory is now equipped with a potent armamentarium of techniques to tackle the study of neuropsychiatric disorders. By joining forces with increasingly powerful techniques for studying human subjects, such as genome-wide association studies and brain imaging (Harrison and Weinberger, 2005; Robbins, 2005; Hariri and Holmes, 2006), the hope is that research using mice can allow us to make some truly novel insights into the pathophysiology and treatment of neuropsychiatric diseases, including schizophrenia.
Arguably, the development of sophisticated, translatable mouse-based assays for the behavioral manifestations of schizophrenia has lagged the advances in molecular and genomic techniques. Contrary to a commonly voiced opinion, we do not believe that this is because mice are “not smart enough” to perform complex behavioral, particularly cognitive, assays, but rather that an adequate investment of time and effort has not been put into adapting and validating procedures for the mouse.
In a collaborative venture with Bussey, Saksida and colleagues, our laboratory has made efforts to fill this gap by investing in the development of novel assays, including adapting a touchscreen-based method for measuring cognitive and executive functions for use in mice (Izquierdo et al., 2006), and by validating existing models of schizophrenia, such as subchronic phencyclidine (PCP) treatment, in the touchscreen system and other mouse assays. We have sought to utilize these assays to elucidate mechanisms subserving complex behaviors and disease-related behavioral dysfunctions. As part of these efforts, we have examined pharmacological models of schizophrenia in our tasks, and recently reported on the effects of subchronic PCP treatment on social behavior and cognition (touchscreen-based visual discrimination and reversal learning) in non-mutant mice (Brigman et al., 2009). Here, we summarize these results and put them in the larger context of ongoing efforts in the field to develop valid models of schizophrenia, or at least assays for some of the main symptoms of the disease, in mice. We begin with a brief overview of how the major symptoms of schizophrenia are clinically categorized and assayed by mouse behavioral tests. We go on to discuss in greater detail various mouse assays for “cognitive flexibility”, including reversal learning – a type of executive function impaired in schizophrenia that we and others have highlighted as a particularly tractable, translatable process to measure in rodent models of schizophrenia. We end with some concluding remarks on some key questions to be addressed in future work.