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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/218778
The role of the synaptic plasticity gene NRN1 in schizophrenia: integrating molecular and neuroimaging approaches
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[eng] Schizophrenia, a psychiatric disorder affecting 24 million people worldwide, continues to present significant challenges despite notable progress in understanding its etiology. While advancements have been made, the fundamental pathophysiological mechanisms, molecular diagnostics, and precise biomarkers remain unclear. Consequently, ongoing psychiatric research must focus on unraveling the complex biological foundations of the disorder. A deeper understanding is crucial for identifying more appropriate diagnostic categories and developing innovative therapeutic strategies to improve the quality of life for individuals affected by schizophrenia.
Currently, the leading etiological hypothesis suggests that schizophrenia arises from a complex interaction between genetic and environmental factors, which disrupt the processes governing brain development and maturation. From birth to adulthood, brain development depends on synaptic plasticity, the process by which neurons modify their connections in response to external signals, refining synapses and creating neural circuits. Accordingly, impaired synaptic plasticity is thought to play a pivotal role in the pathophysiology of schizophrenia, a notion strongly supported by evidence from multiple disciplines.
Among the genes that play crucial roles in both development and adulthood by mediating synaptic plasticity, Neuritin-1 (NRN1) stands out. Prior to this thesis, extensive research using cell and animal models had explored the functions of NRN1 in the brain. In summary, NRN1 regulates apoptosis in proliferative neurons, promotes neuronal migration and synaptic maturation, modulates neurite outgrowth during differentiation, stimulates dendritic arbor growth, stabilizes active synapses, and as previously mentioned, supports synaptic plasticity. Additionally, several studies have highlighted NRN1's neuroprotective effects, its role in enhancing cognitive performance, and its sensitivity to neurotherapeutic agents through epigenetic mechanisms. This body of evidence suggests that NRN1 could be a promising target for developing therapeutic strategies for schizophrenia, as modulating its expression may positively impact brain functioning and, therefore, behavior and patient outcomes. However, despite these promising findings, human research on the role of NRN1 in schizophrenia remained limited, with only two previous studies examining its impact on schizophrenia risk, age at onset, and intelligence quotient.
Given its potential importance, we focused on NRN1 as a key synaptic plasticity gene in schizophrenia, aiming to deepen our understanding of how this mechanism contributes to the disorder and how such knowledge could enhance patient care. To achieve this, we adopted a multilevel approach incorporating various layers of NRN1 molecular diversity. This strategy resulted in four articles that examined the association of NRN1 with age at onset, clinical and neuroimaging traits of schizophrenia, its interactions with related
genes, its expression and methylation in post-mortem brain samples from schizophrenia patients, and its methylation changes in response to cognitive therapy.
Overall, our results validate the efficacy of a multifaceted methodology in uncovering the role of candidate genes in modulating schizophrenia presentation. Specifically, we identified NRN1 genetic variants associated with an increased risk for early-onset schizophrenia-spectrum disorders, with carriers exhibiting altered dorsolateral prefrontal cortex activity during a working memory task. Additionally, epistatic interactions between NRN1, BDNF-rs6265, and CACNA1C-rs1006737 significantly modulated clinical severity and neuroanatomical features, with the interaction between NRN1 and BDNF in the left lateral orbitofrontal cortex fully mediating the effects on general psychopathology. In post-mortem brain samples, schizophrenia patients treated with clozapine displayed lower NRN1 expression and methylation differences in the prefrontal cortex compared to untreated patients and controls, with these methylation differences correlating with NRN1 expression and influenced by specific genetic variants. Lastly, we demonstrated the clinical applicability of our findings, showing that cognitive remediation therapy is associated with changes in NRN1 peripheral methylation, with increased methylation distinguishing responders from non-responders across cognitive domains, an effect also shaped by NRN1 genetic variability.
Globally, the findings presented in this thesis highlight how understanding the role of specific genes involved in synaptic plasticity can not only deepen our insight into the etiology of schizophrenia but also potentially lead to improved patient care. Although studies focusing on candidate genes are constrained by the polygenic nature of the disorder, these studies provide compelling evidence and valuable clinical insights, laying the groundwork for further exploration of these key genes within broader molecular networks. Thus, this thesis serves as a steppingstone in the collective process of building knowledge about the etiology of psychosis, aiming to understand how individual genetic variations influencing neurodevelopment and synaptic plasticity contribute to the underlying causes of schizophrenia.
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ALMODÓVAR PAYÁ, Carmen. The role of the synaptic plasticity gene NRN1 in schizophrenia: integrating molecular and neuroimaging approaches. [consulta: 4 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/218778]