How do established developmental risk-factors for schizophrenia change the way the brain develops?

Abstract

The recognition that schizophrenia is a disorder of neurodevelopment is widely accepted. The original hypothesis was coined more than 30 years ago and the wealth of supportive epidemiologically data continues to grow. A number of proposals have been put forward to suggest how adverse early exposures in utero alter the way the adult brain functions, eventually producing the symptoms of schizophrenia. This of course is extremely difficult to study in developing human brains, so the bulk of what we know comes from animal models of such exposures. In this review, I will summarise the more salient features of how the major epidemiologically validated exposures change the way the brain is formed leading to abnormal function in ways that are informative for schizophrenia symptomology. Surprisingly few studies have examined brain ontogeny from embryo to adult in such models. However, where there is longitudinal data, various convergent mechanisms are beginning to emerge involving stress and immune pathways. There is also a surprisingly consistent alteration in how very early dopamine neurons develop in these models. Understanding how disparate epidemiologically-validated exposures may produce similar developmental brain abnormalities may unlock convergent early disease-related pathways/processes.

Fig. 1. Conceptual models of brain ontogeny and schizophrenia.

Depicted are four scenarios regarding how abnormal brain development could be a causal factor in patients developing schizophrenia. The four options are described in detail in the text. Options 1–3 have all been outlined previously by others. Option 4 is highly speculative and based largely on observations on dopamine ontogeny in animal models of developmental risk factors for schizophrenia. Thereof course may be many other conceptual models for how abnormal brain development alters brain ontogeny contributing to schizophrenia.

Fig. 2. Epidemiologically-validated developmental risk factors for schizophrenia and the convergent processes affecting brain development.

This figure depicts the multiple convergent processes operating across the prominent developmental risk factors for schizophrenia. Almost all exposures increase foetal brain/placental exposure to increased glucocorticoids and inflammatory factors. There are also multiple alterations to early epigenetic factors governing gene expression, with most risk exposures affecting DNA methylation, however certain exposures also affect histone acetylation/methylation and micro RNA production. At a cellular level a surprisingly high number of exposures affect the early ontogeny of dopamine neurons. Effects on the development of other brain cell types i.e. GABA or glutamateric are also affected but reports of alterations to these neurons are far less frequent. Also noted is whether genome-wide environmental interaction (GWEIS) studies have been conducted for these developmental risk exposures. Abbreviations: DA, dopamine; GWEIS, genome wide environment interaction study; HPA, hypo-thalamic pituitary axis; Vit D, vitamin D; Fe²⁺, iron; PUFA, polyunsaturated fatty acids. Increased exposure validated in developing brain/placenta. Weak evidence. X No effect. ? Not studied. Altered DNA methylation. Altered Histone acetylation/methylation. Increased micro-RNA.