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Developmental Origins of Adult Psychiatric Disorders: Insights from Molecular and Cellular Mechanisms Underlying the Assembly of Neural Circuits

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Defense Thèse de privat-docent : Univ. Genève, 2010
Abstract Recent advances in the field of psychiatric genetics suggest that vulnerability to prevalent psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BP) is associated with susceptibility genes playing key roles in neuro-developmental pathways. The hypothesis that SZ may have a neurodevelopmental origin has been advocated for many years. According to this hypothesis, genetic and early life environmental factors could alter brain development as early as the first trimester of gestation but also at later stages of brain maturation and lead to a disruption in the assembly of neural circuits. In a multiple hit model, it is hypothesized that subsequent insults on altered neural circuits with decreased flexibility could exhaust the homeostatic capacity of neural networks and lead to dysfunction and common psychiatric symptoms in adulthood. This theoretical framework involving the concepts of developmental vulnerability and a multiple hit model may also be applied to other psychiatric disorders such as affective disorders. In the first part of this work, we will first expose the clinical, neuroimaging and neuropathological data that support a neurodevelopmental origin to SZ and extend this review to the field of affective disorders. We will then review the recent genetic advances that are in the verge of profoundly modifying our understanding of psychiatric disorders. In the second part of this work, we will describe the cellular processes that are central to the proper formation of brain circuits and illustrate how risk alleles associated with SZ and affective disorders can alter these exquisitely timed-stepped processes and lead to persistent neurodevelopmental alterations. In the last part of this work, we will focus more specifically on the importance of serotonin-related risk alleles associated with affective disorders and discuss the arguments supporting the hypothesis that these risk alleles could operate during brain development and increase vulnerability to stress-related disorders. The pace of discovery of novel risk alleles associated with adult psychiatric disorders is increasing very rapidly with the use of high-throughput genome-wide technologies. As discussed in this work, it will be of critical importance to translate the human genetic findings at a preclinical level in order to elucidate the biological function of risk alleles by combining in vivo genetic manipulation approaches in rodent models and a precise analysis of the molecular and cellular events that participate to the assembly of neural circuits. The hope is that this translational approach will contribute to the establishment of a molecular and cellular etiopathogenesis in psychiatry and lead to novel therapeutical perspectives and interventions.
Keywords PsychiatryDevelopmentCircuitsBipolar disorderSchizophrenia
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Research group Groupe Dayer Alexandre (Formation du circuit cortical) (875)
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DAYER, Alexandre. Developmental Origins of Adult Psychiatric Disorders: Insights from Molecular and Cellular Mechanisms Underlying the Assembly of Neural Circuits. Université de Genève. Thèse de privat-docent, 2010. https://archive-ouverte.unige.ch/unige:5171

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Deposited on : 2010-02-15

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