Neuronal migration abnormalities and its possible implications for schizophrenia

Abstract

Schizophrenia is a complex mental disorder that displays behavioral deficits such as decreased sensory gating, reduced social interaction and working memory deficits. The neurodevelopmental model is one of the widely accepted hypotheses of the etiology of schizophrenia. Subtle developmental abnormalities of the brain which stated long before the onset of clinical symptoms are thought to lead to the emergence of illness. Schizophrenia has strong genetic components but its underlying molecular pathogenesis is still poorly understood. Genetic linkage and association studies have identified several genes involved in neuronal migrations as candidate susceptibility genes for schizophrenia, although their effect size is small. Recent progress in copy number variation studies also has identified much higher risk loci such as 22q11. Based on these genetic findings, we are now able to utilize genetically-defined animal models. Here we summarize the results of neurodevelopmental and behavioral analysis of genetically-defined animal models. Furthermore, animal model experiments have demonstrated that embryonic and perinatal neurodevelopmental insults in neurogenesis and neuronal migrations cause neuronal functional and behavioral deficits in affected adult animals, which are similar to those of schizophrenic patients. However, these findings do not establish causative relationship. Genetically-defined animal models are a critical approach to explore the relationship between neuronal migration abnormalities and behavioral abnormalities relevant to schizophrenia.

Utility and validity of DISC1 mouse models in biological psychiatry

“…As will be discussed later, one caveat of these models might be that the molecular signatures and transcriptional landscape are not clear after these genetic mutations, partly due to the complex nature of Disc1 isoform expression, and potential effects of developmental compensation of the phenotypes caused by these mutations (Brandon and Sawa, 2011; Muraki and Tanigaki, 2015). Further studies are warranted on the circuit-level disturbance and its causal link to subtle behavioral outcomes in these mice.…”

Mechanisms underlying the role of DISC1 in synaptic plasticity

“…). Several excellent reviews on DISC1's role in these processes have been published (Brandon and Sawa, ; Bradshaw & Porteous, ; Wu and Xiao, ; Muraki and Tanigaki, ) and in this review, we focus instead on synaptic plasticity in the adult as a critical process deficient in animals with mutated DISC1. However, we also consider the possibility that DISC1's action in adulthood is the result of modifications that occur at early phases of postnatal development.…”

The role of IL-6 in neurodevelopment after prenatal stress

“…The development of the GABAergic system is significant for multiple brain functions; maturational disruptions have been linked to psychopathologies including Tourette syndrome, schizophrenia, and autism (Pleasure et al, 2000; Yip et al, 2008; Kataoka et al, 2010; Matrisciano et al, 2013). Prenatal stress delays GABAergic progenitor migration from their birthplace in the medial ganglionic eminence to their destination in the cortical plate (Stevens et al, 2013) and GABAergic migration is critical for cortical function (Volk and Lewis, 2013; Muraki and Tanigaki, 2015). The subsequent maturation of GABAergic cells is also affected by prenatal stress and has been linked to altered social and anxiety-like behaviors after prenatal stress (Stevens et al, 2013; Lussier and Stevens, 2016).…”