Schizophrenia (SZ) is a debilitating mental illness with a worldwide lifetime risk of about 1% characterized by positive symptoms (e.g., delusions and hallucinations), negative symptoms (e.g., affective flattening, apathy, and social withdrawal), and cognitive dysfunction. SZ is caused by a combination of genetic factors together with environmental insults, including prenatal infection, perinatal complication, and cannabis use. Recently, SZ has been described simply as a neurodevelopmental disorder [1
]. However, the onset of SZ occurs in young adulthood, in contrast to an earlier onset in childhood that occurs in many other neurodevelopmental disorders, such as autism. In the pathology of SZ, disturbances elicited by genetic susceptibility factors and environmental insults in prenatal and perinatal stages are likely to disturb postnatal brain maturation for many years, which results in the full-blown onset of the disease mainly after puberty [3
Such pathological mechanisms underlying the long time-course of SZ have not yet been fully elucidated. One of the major reasons is the difficulty in designing longitudinal clinical studies for high-risk subjects many years before the disorder is manifested, although a small number of state-of-the-art brain imaging studies exist [4
]. Lack of appropriate animal models to validate working hypotheses for the mechanisms also impedes progress. Although there are several interesting rodent models with specific brain lesions in early development that display phenotypic changes relevant to SZ only after puberty [5
], these models may not exactly replicate the etiologies of SZ.
Recent progress in psychiatric genetics has revealed several promising genetic susceptibility factors for SZ, including Neuregulin-1 (NRG1/Heregulin), the NRG1 receptor ErbB4 (HER4, a receptor tyrosine-protein kinase), and Disrupted-in-Schizophrenia-1 (DISC1) [7
]. The role of NRG1 as a risk factor for SZ has been supported by many association studies in more than one ethnic group [9
]. Compelling genetic evidence for DISC1 was initially obtained from a large Scottish pedigree in which a majority of family members with disruption of DISC1 suffer from psychiatric illnesses, including SZ [10
]. Biological studies have revealed that both NRG1 and DISC1 are multifunctional in nature, with key roles during neurodevelopment [12
]. Therefore, systematic studies with these factors from the time of the initial risks in early development to disease onset after puberty is likely to open a window on a mechanistic understanding of the ‘long-term’ neurodevelopmental processes in SZ.
Over the past three years, excellent review articles for individual risk factors for SZ, such as NRG1/ErbB4 and DISC1, have been published [9
]. Several reviews that discuss animal models for SZ are also available, but with an emphasis on behavioral assays in adult animals [15
]. Nonetheless, as far as we are aware, few reports have addressed mechanistic approaches to long-term neurodevelopmental processes of SZ from the initial risk during pre- and perinatal stages, postnatal brain maturation, to the onset in young adulthood, especially by examining possible convergence of promising SZ genetic susceptibility factors at the functional levels in vivo
. The extraordinary advances in the field over the past 1–2 years enable us to provide an overview of these issues, in particular focusing on the significance of “postnatal maturation” of the frontal cortex and associated circuitry, which are crucial for cognitive functions, such as working memory, and are frequently impaired in SZ patients now. It becomes also possible to discuss how such molecular approaches can suggest novel therapeutic strategies for this devastating disorder. In this review, we first outline long-term neurodevelopmental processes that might be disturbed in SZ (). Then, we describe roles of NRG1-ErbB4 and DISC1 in these processes (), suggesting convergence of these two cascades and finally ending with a discussion of relevant animal models.
Long-term neurodevelopmental processes, which are disturbed in schizophrenia (SZ)
Convergence of two pleiotropic pathways: DISC1 and Neuregulin-1 (NRG1)–ErbB4, which are disturbed in schizophrenia