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GluN3A-NMDA receptors regulate protein synthesis by controlling the assembly of GIT1-mTORC1 complexes


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Título :
GluN3A-NMDA receptors regulate protein synthesis by controlling the assembly of GIT1-mTORC1 complexes
Autor :
Conde-Dusman, Maria J.  
Tutor:
Perez-Otaño, Isabel  
Editor :
Universidad Miguel Hernández
Departamento:
Instituto de Neurociencias
Fecha de publicación:
2021-12-17
URI :
https://hdl.handle.net/11000/29121
Resumen :
Early brain development is characterized by an overproduction of synapses which make weak functional connections between neurons. Neuronal activity later refines this basic circuitry by strengthening and maintaining subsets of connections but suppressing (or “pruning”) others, ultimately resulting in the formation of more precise and durable connections. Growing evidence links even subtle deficits in the balance between synapse maturation and pruning to a variety of severe brain disorders, ranging from autism, schizophrenia or bipolar disorder to neurodegenerative conditions that debut in the adult life. In an effort towards identifying the molecular underpinnings of this prevalent phenomenon of synaptic refinement, NMDA receptors containing GluN3A subunits (GluN3A-NMDARs) have emerged as key regulators. GluN3A-NMDARs are typically expressed before and during critical periods of postnatal development, prevent premature synapse maturation/ stabilization until the arrival of sensory experience, and later target less or non-used synapses for pruning. However, the cell biological and signaling mechanisms whereby GluN3A ensures correct synapse selection and its coupling to experience are yet poorly understood. Previous work of our lab revealed that GluN3A-NMDARs sequester the scaffolding protein GIT1 and interfere with the restructuring of the actin cytoskeleton in spines. Moreover, GluN3A-NMDARs selectively inhibits the induction of a subset of activity- and NMDAR-regulated signaling pathways. The mTOR pathway, and specifically the multiprotein complex mTORC1, stands out within this group because of its central role in driving dendritic protein synthesis in response to synaptic signals. Both actin remodeling and protein synthesis are thought to be required for the conversion of relevant experiences into enduring memories by driving long-lasting structural changes that stabilize synaptic contacts. Building on this work, here we investigate how GluN3A-NMDARs inhibit synaptic signaling to the multiprotein complex mTORC1 and evaluate its consequences on protein synthesis during postnatal development and memory encoding. We find that mTORC1 inhibition is mediated by direct binding of GluN3A to GIT1, which impedes the assembly of a new type of mTOR signaling complex composed of GIT1, mTOR and Raptor (termed GIT1-mTORC1). GIT1-mTORC1 complexes are located at or near synaptic sites and couple synaptic stimulation to mTORC1-dependent protein synthesis, providing a site for nucleating mTOR responses at individual synapses. Developmental or genetic loss of GluN3A enables GIT1-mTOR complex formation, potentiates mTORC1 signaling and enhances protein synthesis. Enhanced activity of the protein synthesis machinery correlates with enhanced long-term memory (LTM) formation in the conditioned taste aversion paradigm that is manifest after light training and reversed by the mTOR inhibitor rapamycin. Together, these findings uncover a major role of GIT1 and GluN3A-NMDARs in setting local modes of protein synthesis with implications for the development of precise neural circuits and adult cognitive processing.
Palabras clave/Materias:
Neurobiología
Área de conocimiento :
CDU: Ciencias aplicadas: Medicina: Patología. Medicina clínica. Oncología: Neurología. Neuropatología. Sistema nervioso
Tipo documento :
application/pdf
Derechos de acceso:
info:eu-repo/semantics/openAccess
Aparece en las colecciones:
Tesis doctorales - Ciencias de la Salud



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