Schizophrenia (SCZ) and bipolar disorder (BPD) are major mental illnesses with onset in adulthood. Although the clinical manifestation and disease course are substantially different from each other, these two disorders share genetic risks at several loci and have some similarities in the patterns of cognitive impairment (Berrettini, 2004
; Craddock et al., 2006
; Hill et al., 2008
To address molecular mechanisms underlying mental illnesses, many groups have studied molecular expression profiles in postmortem brains and other tissues from patients compared with those from normal controls. Since 2000, in addition to candidate molecule approaches, an unbiased methodology for expression study with microarrays has been frequently employed (Horvath et al., 2011
; Mirnics et al., 2006
; Mirnics et al., 2000
). More recently, RNA-seq has been introduced as a revolutionary tool for transcriptomics (Twine et al., 2011
; Wang et al., 2009
). At the protein level, several types of proteomic approaches are also utilized (English et al., 2011
; Wittmann-Liebold et al., 2006
). A major concern in these molecular profile studies is that this approach may not be able to address brain circuitry-dependent mechanisms.
To complement this limitation, rodents (rats and mice) are used to model mental diseases (Chen et al., 2006
; Cryan and Holmes, 2005
; Nestler and Hyman, 2010
). These models have been characterized primarily by behavioral changes: for example, hyperlocomotion, social interaction deficits, impaired prepulse inhibition, and working memory deficits in rodents are used as indicators of behavioral deficits possibly corresponding to positive symptoms, negative symptoms, disturbance in information processing, and cognitive deficits in SCZ patients, respectively (Arguello and Gogos, 2006
). In addition, mild but significant abnormalities in anatomy and histology are used as translatable characteristics between mice and humans, including enlarged ventricles, dendritic changes, and interneuron deficits (Jaaro-Peled et al., 2010
). Nonetheless, due to the uncertain etiology of mental illnesses, the construct and etiological validity of these models is always debated. The models that modulate genes whose expression is altered in patient tissues may reflect disease pathophysiologies, although there is no guarantee that the model really mimics disease etiologies. Such animal models may complement the difficulty to study brain circuitry-dependent mechanisms at functional levels using expression studies of patient cells and tissues. For example, transient overexpression of dopamine D2 receptor specifically in the striatum can cause persistent functional abnormalities in the prefrontal cortex, affecting some endophenotypes relevant to schizophrenia (Kellendonk et al., 2006
), while transient knockdown of DISC1 specifically in the cells of pyramidal neuron lineage in the developing cortex affects postnatal mesocortical dopaminergic maturation and causes functional deficits in mesolimbic dopaminergic neurons, leading to neurochemical and behavioral deficits relevant to SCZ in adulthood (Niwa et al., 2010
). These two papers may support the idea of how gene manipulations in mice can provide us with clues to our understanding of circuitry-based mechanisms of mental illnesses. Specific targets found in human gene expression studies can be a source for genetic mouse models that could further enhance such insight into the mechanisms underlying mental illnesses.
In this review, we first summarize DNA microarray studies in postmortem brains from patients with SCZ and BPD. From the many genes in the literature we discuss those that have been found to change in more than one study. In the second part, we review mouse models built by modulating genes that have been identified in human brain gene expression studies. Finally, we discuss a promising research strategy for better understanding major mental illnesses by combining human molecular profiling and studies with mouse models.