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. 2020 Mar:217:95-104.
doi: 10.1016/j.schres.2019.08.036. Epub 2019 Sep 12.

Neurodevelopmental concepts of schizophrenia in the genome-wide association era: AKT/mTOR signaling as a pathological mediator of genetic and environmental programming during development

Kristy R Howell  1 , Amanda J Law  2
Affiliations

Neurodevelopmental concepts of schizophrenia in the genome-wide association era: AKT/mTOR signaling as a pathological mediator of genetic and environmental programming during development

Kristy R Howell et al. Schizophr Res. 2020 Mar.

Abstract

Normative brain development is contingent on the complex interplay between genes and environment. Schizophrenia (SCZ) is considered a highly polygenic, neurodevelopmental disorder associated with impaired neural circuit development, neurocognitive function and variations in neurotransmitter signaling systems, including dopamine. Significant evidence, accumulated over the last 30 years indicates a role for the in utero environment in SCZ pathophysiology. Emerging data suggests that changes in placental programming and function may mediate the link between genetic risk, early life complications (ELC) and adverse neurodevelopmental outcomes, with risk highlighted in key developmental drivers that converge on AKT/mTOR signaling. In this article we overview select risk genes identified through recent genome-wide association studies of SCZ including AKT3, miR-137, DRD2, and AKT1 itself. We propose that through convergence on AKT/mTOR signaling, these genes are critical factors directing both placentation and neurodevelopment, influencing risk for SCZ through dysregulation of placental function, metabolism and early brain development. We discuss association of risk genes in the context of their known roles in neurodevelopment, placental expression and their possible mechanistic links to SCZ in the broad context of the 'developmental origins of adult disease' construct. Understanding how common genetic variation impacts early fetal programming may advance our knowledge of disease etiology and identify early critical developmental windows for prevention and intervention.

Keywords: Developmental origins of disease; GWAS; Placenta; Schizophrenia.

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Conflict of interest statement

Declaration of competing interest The authors declare no conflict of interest. This work was supported by the National Institute of Mental Health under Award Number R01MH103716 (AJL). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Figures

Figure 1.
Figure 1.
Proposed DOHaD model of SCZ. Through convergence on reduced AKT/mTOR signaling, risk variants in AKT1, AKT3, miR-137 and DRD2 propagates abnormal ontogenic programming mechanisms. Resulting phenotypes have all been linked to SCZ. We propose that genes for SCZ are critical factors directing both placental function and neurodevelopment, influencing risk for SCZ through differential roles in placentation, placental metabolism and early brain development.
See this image and copyright information in PMC

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