Neurodevelopmental disturbances in schizophrenia: evidence from genetic and environmental factors

Abstract

Since more than 3 decades, schizophrenia (SZ) has been regarded as a neurodevelopmental disorder. The neurodevelopmental hypothesis proposes that SZ is associated with genetic and environmental risk factors, which influence connectivity in neuronal circuits during vulnerable developmental periods. We carried out a non-systematic review of genetic/environmental factors that increase SZ risk in light of its neurodevelopmental hypothesis. We also reviewed the potential impact of SZ-related environmental and genetic risk factors on grey and white matter pathology and brain function based on magnetic resonance imaging and post-mortem studies. Finally, we reviewed studies that have used patient-derived neuronal models to gain knowledge of the role of genetic and environmental factors in early developmental stages. Taken together, these studies indicate that a variety of environmental factors may interact with genetic risk factors during the pre- or postnatal period and/or during adolescence to induce symptoms of SZ in early adulthood. These risk factors induce disturbances of macro- and microconnectivity in brain regions involving the prefrontal, temporal and parietal cortices and the hippocampus. On the molecular and cellular level, a disturbed synaptic plasticity, loss of oligodendrocytes and impaired myelination have been shown in brain regions of SZ patients. These cellular/histological phenotypes are related to environmental risk factors such as obstetric complications, maternal infections and childhood trauma and genetic risk factors identified in recent genome-wide association studies. SZ-related genetic risk may contribute to active processes interfering with synaptic plasticity in the adult brain. Advances in stem cell technologies are providing promising mechanistic insights into how SZ risk factors impact the developing brain. Further research is needed to understand the timing of the different complex biological processes taking place as a result of the interplay between genetic and environmental factors.

Effects of prenatal maternal immune activation and exposure to circadian disruption during adolescence: exploring the two-hit model of neurodevelopmental disorders

“…Schizophrenia (SCZ) and autism spectrum disorders (ASDs) are neurodevelopmental disorders, each affecting approximately 1% of the global population (1,2). Neurodevelopmental disorders result from complex interactions between genetic and environmental risk factors, which are thought to disturb normal brain development, ultimately leading to the clinical occurrence of these disorders (3)(4)(5). Current research increasingly focuses on the combined impact of multiple risk factors for neurodevelopmental disorders, rather than examining them in isolation (6).…”

Arginine vasopressin activates serotonergic neurons in the dorsal raphe nucleus during neonatal developmentin vitroandin vivo

“…One of the early risk factors are obstetric complications including long and complicated labour or mild birth asphyxia that cause stress to the infant and make individuals more susceptible to psychiatric disorders such as affective disorders or schizophrenia (Nosarti et al, 2012; Schmitt et al, 2014; Buoli et al, 2016; Belbasis et al, 2018; Álvarez-García et al, 2022; Schmitt et al, 2023). Birth stress, in common with other ELAs such as neglect or abuse, leads to strong activation of the neonatal stress axis during a sensitive period of brain development.…”

A Systematic Review of the Human Accelerated Regions in Schizophrenia and Related Disorders: Where the Evolutionary and Neurodevelopmental Hypotheses Converge

“…Although the specific aetiological and pathophysiological mechanisms have not yet been fully elucidated, the amount of evidence regarding environmental and genetic risk factors converging in neurodevelopmental pathways [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ], has led to the neurodevelopment hypothesis of the origin of the disorder and its posterior revisions. Currently, this hypothesis states that the joint and interacting effect of the polygenic background and environmental stressors disrupt the neurodevelopment and brain maturation trajectories and underlie the later emergence of schizophrenia [ 8 , 9 , 10 , 11 ].…”