Suchergebnisse

La eficacia de los valores, principios y derechos consagrados en la Constitución, está ligada a la concepción antropológica del Estado social de Derecho, que surge de la interpretación del enunciado normativo de la dignidad humana, conforme lo expresa la Corte Constitucional en la sentencia T–881 de 2002. Sin embargo, al estudiar los fallos relacionados en la sentencia T–881 del 2002, en los que se apoyó el alto Tribunal para delimitar el alcance del enunciado normativo de la dignidad humana, formulado bajo un triple carácter de valor, principio y derecho, y su estrecha relación con el tercer imperativo kantiano, se advierte que no existe corrección en dicha interpretación.Para examinar la consistencia del argumento, expuesto por la Corte Constitucional en la referida providencia, en esta investigación se hace primero un análisis descriptivo de la misma, luego se revisa cada uno de los fallos, fundamento de las premisas, y, por último, se confrontan estas con las teorías filosóficas correspondientes.

The regulated trafficking of AMPA-type glutamate receptors (AMPARs) from dendritic compartments to the synaptic membrane in response to neuronal activity is a core mechanism for long-term potentiation (LTP). However, the contribution of the microtubule cytoskeleton to this synaptic transport is still unknown. In this work, using electrophysiological, biochemical, and imaging techniques, we have found that one member of the kinesin-3 family of motor proteins, KIF13A, is specifically required for the delivery of AMPARs to the spine surface during LTP induction. Accordingly, KIF13A depletion from hippocampal slices abolishes LTP expression. We also identify the vesicular protein centaurin-α1 as part of a motor transport machinery that is engaged with KIF13A and AMPARs upon LTP induction. Finally, we determine that KIF13A is responsible for the remodeling of Rab11-FIP2 endosomal structures in the dendritic shaft during LTP. Overall, these results identify specific kinesin molecular motors and endosomal transport machinery that catalyzes the dendrite-to-synapse translocation of AMPA receptors during synaptic plasticity. ; Spanish Ministry of Science and Innovation (grants SAF2014-57233-R and SAF2017-86983-R) and the European Union (PCIN-2016-095) to J.A. Esteban, and by the Institut National de la Santé et de la Recherche Médicale, Institut Curie, and the Centre National de la Recherche Scientifique (LabEx Cell(n)Scale, ANR-11-LABX-0038) to C. Delevoye. Y. Gutiérrez and S. López-García are recipients of predoctoral contracts from the Spanish Ministry of Education

It is well­-established that Rab11-dependent recycling endosomes drive the activity-dependent delivery of AMPA receptors (AMPARs) into synapses during long-term potentiation (LTP). Nevertheless, the molecular basis for this specialized function of recycling endosomes is still unknown. Here, we have investigated RAB11FIP2 (FIP2 hereafter) as a potential effector of Rab11-dependent trafficking during LTP in rat hippocampal slices. Surprisingly, we found that FIP2 operates independently from Rab11 proteins, and acts as a negative regulator of AMPAR synaptic trafficking. Under basal conditions, FIP2 associates with AMPARs at immobile compartments, separately from recycling endosomes. Using shRNA-mediated knockdown, we found that FIP2 prevents GluA1 (encoded by the Gria1 gene) AMPARs from reaching the surface of dendritic spines in the absence of neuronal stimulation. Upon induction of LTP, FIP2 is rapidly mobilized, dissociates from AMPARs and undergoes dephosphorylation. Interestingly, this dissociation of the FIP2¿AMPAR complex, together with FIP2 dephosphorylation, is required for LTP, but the interaction between FIP2 and Rab11 proteins is not. Based on these results, we propose a retention¿release mechanism, where FIP2 acts as a gate that restricts the trafficking of AMPARs, until LTP induction triggers their release and allows synaptic delivery. ; Ministerio de Ciencia, Innovación y Universidades (Spanish Ministry of Science, Innovation and Universities) (SAF2015-72988-EXP, SAF2017-86983-R) and the European Union Joint Programming Initiative A healthy diet for a healthy life (PCIN-2016-095). M.R. and Y.G. were recipients of pre-doctoral contracts from the Instituto de Salud Carlos III and from the Ministerio de Educación, Cultura y Deporte (Spanish Ministry of Education, Culture and Sport)

The synaptic removal of AMPA-type glutamate receptors (AMPARs) is a core mechanism for hippocampal long-term depression (LTD). In this study, we address the role of microtubule-dependent transport of AMPARs as a driver for vesicular trafficking and sorting during LTD. Here, we show that the kinesin-1 motor KIF5A/C is strictly required for LTD expression in CA3-to-CA1 hippocampal synapses. Specifically, we find that KIF5 is required for an efficient internalization of AMPARs after NMDA receptor activation. We show that the KIF5/AMPAR complex is assembled in an activity-dependent manner and associates with microsomal membranes upon LTD induction. This interaction is facilitated by the vesicular adaptor protrudin, which is also required for LTD expression. We propose that protrudin links KIF5-dependent transport to endosomal sorting, preventing AMPAR recycling to synapses after LTD induction. Therefore, this work identifies an activity-dependent molecular motor and the vesicular adaptor protein that executes AMPAR synaptic removal during LTD. ; Spanish Ministry of Science (SAF2017-86983-R, PID2020-117651RB) to J.A.E. A.L., Y.G., and A.F.-R. were recipients of predoctoral contracts from the Spanish Ministry of Science. A.B. was funded by the European Union (Marie Curie Intra-European Fellowship program). F.F.H. was funded by the Deutsche Forschungsgemeinschaft (DFG) project 416580360 and HE8413/1-1 and by the Ritz-Stiftung. M.K. was funded by the DFG grants FOR2419 project KN556/11-1 and KN556/11-2