Novel molecular mechanisms contributing to cognitive impairment in schizophrenia
[eng] Schizophrenia is a neuropsychiatric syndrome that affects around 1% of the world population (Marder & Cannon, 2019). Its age of onset typically occurs within the second and third decades of life (Velligan & Rao, 2023). It is characterized by the presence of psychosis (e.g. hallucinatio...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/224857 |
| Acceso en línea: | https://hdl.handle.net/2445/224857 http://hdl.handle.net/10803/696113 |
| Access Level: | acceso embargado |
| Palabra clave: | Neurociències Esquizofrènia Hipocamp (Cervell) Micro RNAs Cognició Neurosciences Schizophrenia Hippocampus (Brain) MicroRNAs Cognition |
| Sumario: | [eng] Schizophrenia is a neuropsychiatric syndrome that affects around 1% of the world population (Marder & Cannon, 2019). Its age of onset typically occurs within the second and third decades of life (Velligan & Rao, 2023). It is characterized by the presence of psychosis (e.g. hallucinations, delusions and disorganized speech), negative symptoms (e.g. social withdrawal, anhedonia and apathy), and cognitive deficits (e.g. social cognition deficits, impaired executive functions and working memory) (Marder & Cannon, 2019). Antipsychotic treatments can help to manage positive symptoms during acute episodes. However, their side effects and limited benefits on sociability and cognition often result in poor medication adherence and increased risk of relapse. Consequently, there is a significant unmet medical need, particularly for treatments targeting those cognitive symptoms that emerge in the premorbid phase and affect nearly 98% of patients (Harvey et al., 2022; Mihaljević-Peleš et al., 2019). The complexity of the disease relies not only on its wide variety of symptoms, but also from the different heritable and environmental risk factors that influence the development of schizophrenia (Marder & Cannon, 2019; McCutcheon et al., 2020; Jauhar et al., 2022). Research made over the last decades has identified several molecular pathways impaired in the disorder, with neurochemical disturbances related to the dopaminergic and glutamatergic systems having a prominent role in its pathophysiology (Jauhar et al., 2022). Recent evidence has revealed that impaired GABAergic and serotoninergic neurotransmission, neurodevelopmental abnormalities and inflammation could also play a role in the onset and progression of schizophrenia (De Jonge et al., 2017; Gaitonde et al., 2024; Marder & Cannon, 2019; Jauhar et al., 2022; E. E. Lee et al., 2017; Hong & Bang, 2020). Although anatomical and functional dysfunctions have been found in different brain areas from diseased patients, the hippocampus has been suggested to play a pivotal role. Different morphological, electrophysiological, synaptic and molecular impairments affecting this brain region have been associated to schizophrenia and in close relation with to some of its positive, negative and cognitive symptoms (Harrison, 2004; Wegrzyn et al., 2022). Notwithstanding the progresses made to enhance our comprehension of this illness, there remains a need for novel approaches and improved translational models that may recapitulate more accurately its underlying pathological mechanisms. Latest reports have found altered levels of small RNAs (sRNAs) in post-mortem brain samples of patients affected by schizophrenia and other neuropsychiatric disorders (Yoshino & Dwivedi, 2020). sRNAs are non-coding RNAs with less than 200 nucleotides that do not code for proteins but play an essential role regulating messenger RNA (mRNA) expression, stability and translation, with an important function in health and disease (Yoshino & Dwivedi, 2020). Among the different sRNA biotypes, microRNAs (miRNAs) have been linked to the aetiology of schizophrenia through their direct regulation of neurotransmission and immunological pathways that are known to be altered in the disorder (Zhang et al., 2023; Thomas & Zakharenko, 2021). Moreover, dysregulation of some miRNAs has been found not only in the hippocampus, but also in circulating blood vesicles of affected individuals in association with treatment-resistance and the severity of cognitive symptoms (Barnett et al., 2023). However, most of these studies are largely descriptive and none of them has been able to directly assess the potential contribution of sRNAs to the onset and/or progression of the cognitive deficits associated with schizophrenia. Also, genome-wide association studies (GWAS) have found different gene variants associated to cognitive impairment in schizophrenia (Zhao et al., 2022). Some of these risk gene polymorphisms have been located at the forkhead-box P2 (FOXP2) gene, which encodes for a transcription factor involved in regulating synaptic plasticity, neurotransmission and the development of neurons related to language and memory function (Vernes et al., 2007; Lang et al., 2019). FOXP2 has been linked to schizophrenia vulnerability, auditory hallucinations and cognitive deficits in chronic patients with the disorder (Sanjuán et al., 2006; Lang et al., 2019; Sanjuán et al., 2021), although the association of some specific polymorphisms to the disease are still controversial. Furthermore, increased FOXP2 levels have been found in some experimental models of schizophrenia. Nevertheless, it remains to be confirmed whether FOXP2 could mediate the development of the different symptoms associated with schizophrenia and its underlying molecular mechanisms. In this thesis, we hypothesise that sRNAs dysregulated in the hippocampus of patients with schizophrenia are important contributors to its associated cognitive deficits. Furthermore, we aim to decipher whether altered levels of FOXP2 in the brain of these patients could play a role in the onset and progression of some of those clinical features of the disorder. Characterization of hippocampal sRNA profiles from patients with schizophrenia revealed novel microRNA (miRNA) species dysregulated in the disorder. To define the contribution of sRNAs to the cognitive-like symptoms of schizophrenia, we developed a novel translational model based on the injection of those sRNAs isolated from the hippocampus of schizophrenia patients or non-affected individuals into the brain of wild-type mice. Animals receiving sRNAs from diseased patients exhibited an impairment in hippocampal-dependent spatial short-term memory in the T-maze test, in comparison with mice receiving sRNAs from healthy controls or vehicle. However, no deficits were found in recognition memory when performing the novel object recognition (NOR) test, along with no changes in anxiety-like levels nor locomotor activity in the open field test. Golgi staining revealed that schizophrenia sRNAs induced a decrease in the spine density of the pyramidal neurons from the cornus ammonis 1 (CA1) hippocampal region. Injected mice showed higher levels of synaptotagmin 2, a presynaptic marker for inhibitory interneurons. This increase mirrors observations made in patients. Furthermore, we also detected subtle morphological changes in mouse hippocampal microglia in response to sRNAs from affected individuals. We found increased FOXP2 protein levels in the hippocampus and putamen of patients with schizophrenia. These aberrant levels of FOXP2 were recapitulated in the hippocampus, but not in the striatum, of a chronic ketamine mouse model of experimental psychosis. Overexpression of Foxp2 in the hippocampus of wild-type mice using adeno-associated viral (AAV) vectors induced some positive-like symptoms of the disease, such as hyperlocomotion and alterations in navigation in the open field test. No effects in the negative-like symptoms were found in the three-chamber sociability test. Interestingly, Foxp2 overexpression induced cognitive deficits related to an impairment in recognition memory in the NOR test, while we did not find any differences in the spatial short-term memory when performing the T-maze test. Proteomic analysis of the hippocampus of mice overexpressing Foxp2 revealed a reduction in relevant proteins involved in glutamatergic and GABAergic neurotransmission. Positive correlation between FOXP2 and SYT2 protein levels in the hippocampus of affected individuals suggests these changes could be concomitant processes in the disorder. In summary, our results suggest that dysregulated hippocampal sRNAs in schizophrenia are important contributors to its associated cognitive symptoms, while aberrantly increased levels of FOXP2 in the hippocampus of these patients participate in the pathophysiology of the disorder. |
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