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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/202289
Analysis of the impact of synaptic plasticity genes and Human Accelerated Regions on brain function and structure: from the healthy brain to schizophrenia
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[eng] Schizophrenia is a severe psychiatric disorder affecting around 24 million people worldwide. While we begin to disentangle the biological actors implicated in the origin of the disorder, the precise aetiological mechanisms remain largely unknown. Therefore, psychiatry research efforts still need to focus on a better understanding of the complex biological foundations of the disorder to achieve more precise diagnoses and the development of novel therapeutic strategies improving the patients’ quality of life.
The prevailing etiopathological hypothesis considers that schizophrenia originates from the interplay between subtle genetic and environmental insults that disrupt the perfectly orchestrated mechanisms guiding neurodevelopment. Additionally, from an evolutionary perspective, it is suggested that schizophrenia represents a costly trade-off in the evolution of human-specific ontogenic neurodevelopmental processes sustaining the inherent complexity and variability of brain functioning, cognition, and behaviour. Along the neurodevelopmental process, the synapse formation and the organisation and maturation of neural circuits anchor the emergence of distinctive human cortical brain functions. In turn, multidisciplinary evidence indicates that synaptic alterations participate in brain dysfunctions, eventually leading to the emergence of the symptoms and cognitive deficits of schizophrenia. Accordingly, it is suggested that synaptic plasticity impairments play a critical role in the pathophysiology of the disorder.
Among genes converging in neurodevelopmental and synaptic plasticity pathways, there are genes mediating signalling pathways involved in neural homeostasis, dendritic spine development and neural excitability, such as KCNH2, DISC1, CACNA1C and ZNF804A, all of them previously associated with the risk for schizophrenia. Moreover, evolutionary approaches have identified regions that accumulated human-specific changes since the divergence from chimpanzees, like Human Accelerated Regions (HARs). These regions act as transcriptional regulatory elements that endow human neurodevelopment with unique characteristics and harbour schizophrenia genetic susceptibility variants. To facilitate the identification of the genetic and biological mechanisms involved in schizophrenia aetiology, the use of brain-based intermediate phenotypes is a valuable strategy.
Following two approaches centred on the genetic-phenotypic correlates of synaptic plasticity candidate genes and HARs sequences in the brain-based alterations in schizophrenia, this thesis includes four original articles and one systematic review. In these articles, we report the effect of common polymorphisms in KCNH2, DISC1, CACNA1C and ZNF804A genes and the polygenic load of HARs-informative sets on the differences observed between healthy brains and brains with schizophrenia.
Overall, the results validate the efficacy of neuroimaging phenotypes to identify the genetic determinants of schizophrenia and point out the complementarity of candidate genes and genome-wide approaches in the study of the genetic architecture of the disorder. First, we describe the role of KCNH2 and DISC1 genetic variability in modulating the attentional and working memory-related functional responses in a diagnosis- dependent manner. Furthermore, we identify that the epistasis between two schizophrenia GWAS-associated genes, CACNAC1C and ZNF804A, influence the functional ability to adapt to increased working memory difficulty euqally in healthy controls and patients with schizophrenia. Second, we present a review of how HARs underlie human neurodevelopmental signatures, brain configuration, functioning and susceptibility behind psychiatric disorders. Likewise, we report the modulatory effect of HARs polygenicity on brain cortical architectural differences in schizophrenia and provide evidence on the importance of foetal-active regulatory HARs in patients' cortical surface area variability.
Globally, the findings exposed in this thesis point towards the fact that the aetiological foundations of schizophrenia are related to the individual genetic differences altering neurodevelopment and synaptic plasticity trajectories but also to the genomic make-up that defines us as a species. This thesis provides a drop in the ocean of knowledge on disorders inherently linked to the human condition and has sought to comprehend the unique characteristics of our brain to help unravel what it means to be human.
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GUARDIOLA RIPOLL, Maria. Analysis of the impact of synaptic plasticity genes and Human Accelerated Regions on brain function and structure: from the healthy brain to schizophrenia. [consulta: 7 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/202289]