Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1–ErbB4 and DISC1

Schizophrenia (SZ) is primarily an adult psychiatric disorder in which disturbances caused by susceptibility genes and environmental insults during early neurodevelopment initiate neurophysiological changes over a long time course, culminating in the onset of full-blown disease nearly two decades later. Aberrant postnatal brain maturation is an essential mechanism underlying the disease. Currently, symptoms of SZ are treated with anti-psychotic medications that have variable efficacy and severe side effects. There has been much interest in the prodromal phase and the possibility of preventing SZ by interfering with the aberrant postnatal brain maturation associated with this disorder. Thus, it is crucial to understand the mechanisms that underlie the long-term progression to full disease manifestation to identify the best targets and approaches towards this goal. We believe that studies of certain SZ genetic susceptibility factors with neurodevelopmental implications will be key tools in this task. Accumulating evidence suggests that neuregulin-1 (NRG1) and disrupted-in-schizophrenia-1 (DISC1) are probably functionally convergent and play key roles in brain development. We provide an update on the role of these emerging concepts in understanding the complex time course of SZ from early neurodevelopmental disturbances to later onset and suggest ways of testing these in the future.

Introduction

Schizophrenia (SZ) is a debilitating mental illness with a worldwide lifetime risk of approximately 1% and 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 and environmental insults, including prenatal infection, perinatal complication and cannabis use. Recently, SZ has been described simply as a neurodevelopmental disorder 1, 2. However, the onset of SZ occurs in young adulthood, in contrast to earlier onset in childhood for many other neurodevelopmental disorders such as autism. In the pathology of SZ, disturbances caused by genetic susceptibility factors and environmental insults in prenatal and perinatal stages are likely to disturb postnatal brain maturation for many years, resulting in full-blown onset of the disease mainly after puberty [3].

The 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 manifest, although a small number of state-of-the-art brain imaging studies have been carried out [4]. A lack of appropriate animal models to validate working hypotheses for the mechanisms has also impeded progress. Although several interesting rodent models with specific brain lesions in early development exhibit phenotypic changes relevant to SZ after puberty 5, 6, these models might not exactly replicate the etiology 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, 8. 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, 11. Biological studies have revealed that both NRG1 and DISC1 are multifunctional in nature, with key roles during neurodevelopment 12, 13, 14. Therefore, systematic studies of 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 3 years, excellent review articles of individual risk factors for SZ, such as NRG1–ErbB4 and DISC1, have been published 9, 12, 13, 14. 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 to postnatal brain maturation to 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, we focus 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. It is 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 (Figure 1). Then we describe roles of NRG1–ErbB4 and DISC1 in these processes (Figure 2), suggesting convergence of these two cascades, and end with a discussion of relevant animal models.