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Díez Guerra, F. JavierSupervisor

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Papel de Neurogranina en la regulación de la señalización de Calcio/Calmodulina y su impacto en la plasticidad neuronal

Date read: 2024-07-05 {_iPublic_txt_centro_}: | ID: 10486/715418

Author: Martinez Blanco, Elena

Director: Díez Guerra, F. Javier

Abstract

Esta tesis tiene embargado el acceso al texto completo hasta el 05-01-2026 (General); Cognitive functions, such as memory and learning, are based on the ability of neurons to adapt to individual experiences, known as synaptic plasticity. Despite decades of study, the molecular mechanisms underlying plasticity are still poorly understood. Ca2+/CaM-mediated signaling plays a crucial role in this process, and the protein Neurogranin (Ng) modulates this signaling by regulating CaM availability locally and temporally. Ng is closely linked to plasticity and metaplasticity processes. In contexts of cognitive decline, such as aging or neurodegenerative diseases, a decrease in Ng expression is observed, which is often associated with synaptic dysfunction and alterations in Ca2+/CaM signaling. Better understanding the mechanisms regulating neuronal plasticity could provide opportunities to treat cognitive decline associated with these pathological conditions. In this dissertation, we evaluated how Ng expression levels and culture conditions that promote increased synaptic activity affect connectivity and long-term survival of hippocampal neurons. In addition, we identified a regulation in the expression of synaptic plasticity-related proteins in the presence of Ng. Using imaging techniques to analyze intracellular calcium dynamics, together with electrophysiology, we demonstrate that Ng expression increases synaptic activity of neuronal networks and reduces neuronal excitability, suggesting homeostatic adaptation or synaptic scaling. In addition, we developed the CaMK2AR sensor as a reliable marker of Ca2+/CaM signaling. This biosensor is sensitive and specific for CaMKII activity, a key protein in Ca2+/CaM signaling and synaptic plasticity. We observed that CaMKII activity is affected by the presence of Ng and is dependent on free CaM levels. We discuss these results in relation to previous findings suggesting a regulatory role of Ng in synaptic excitability. In summary, this study contributes to the understanding of the mechanisms that maintain synaptic homeostasis and highlights the role of Ng as an important neuroprotective factor (Summary)

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