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SAF2010-21723

Financiado

FORMACION Y REFINAMIENTO DE LOS CIRCUITOS NEURALES

DURING NERVOUS SYSTEM DEVELOPMENT, NEURONS GENERATE MORE AXONAL PROCESSES THAN ULTIMATELY SURVIVE; SOME OF THESE AXONAL BRANCHES ARE PRUNED, WHEREAS OTHERS ARE STABILIZED TO CONSTITUTE A MATURE NEURONAL NETWORK, RELATIVELY LITTLE... ver más

01/01/2010

CSIC

260K€

Presupuesto del proyecto: 260K€

Líder del proyecto

AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGA... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 2-3 | 552M€

Financiación concedida El organismo AGENCIA ESTATAL DE INVESTIGACIÓN notifico la concesión del proyecto el día 2010-01-01 No tenemos la información de la convocatoria

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CSIC

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Líder del proyecto

AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGA... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 2-3 | 552M€

Presupuesto del proyecto 260K€

Descripción del proyecto DURING NERVOUS SYSTEM DEVELOPMENT, NEURONS GENERATE MORE AXONAL PROCESSES THAN ULTIMATELY SURVIVE; SOME OF THESE AXONAL BRANCHES ARE PRUNED, WHEREAS OTHERS ARE STABILIZED TO CONSTITUTE A MATURE NEURONAL NETWORK, RELATIVELY LITTLE IS KNOWN ABOUT THE MOLECULAR MECHANISMS THAT CONTROL AXONAL REMODELING AND SYNAPSE REFINEMENT, THE STUDY OF CONDITIONAL-MUTANT MICE USING THE CRE/LOXP RECOMBINATION SYSTEM HAS ALLOWED US THE PRODUCTION OF MICE LACKING A GENE OF INTEREST IN A TISSUE OR CELL-TYPE SPECIFIC-MANNER, IN THE CONTEXT OF AXONAL DEVELOPMENT, WE HAVE DEMONSTRATED THAT, FIRST FOCAL ADHESION KINASE (FAK) IS INVOLVED IN HIPPOCAMPAL AXONAL TARGETING BY MODULATING AXONAL DYNAMICS THROUGH ACTIN NUCLEATION, SECOND, WE HAVE SHOWN THAT FAK MEDIATES HIPPOCAMPAL AXONAL PRUNING TRIGGERED BY SEMAPHORIN 3A, IN THE CONTEXT OF SYNAPSE FORMATION, WE HAVE DEMONSTRATED TWO SIGNALING PATHWAYS, WHICH ARE INVOLVED IN DIFFERENT ASPECTS OF GABAERGIC SYNAPSE FORMATION, FIRST, WE HAVE SHOWN THAT BDNF-TRKB REGULATES GABAERGIC SYNAPSE MATURATION THROUGH TRANSCRIPTIONAL REGULATION OF GAD65, ONE OF THE GABA SYNTHESIS ENZYME, SECOND, WE HAVE DEMONSTRATED THAT NRG1-ERB4 SIGNALING IS INVOLVED IN GABAERGIC CIRCUITRY FORMATION AT TWO SUBCELLULAR LEVELS, PRE- (CHANDELIER SYNAPSES) AND POST-SYNAPTIC (PARVALBUMIN INTERNEURONS RECEIVING EXCITATORY SYNAPSES), THE AIM OF THIS PROPOSAL IS TO CHARACTERIZE THE MOLECULAR MECHANISMS BY WHICH FAK AND NRG1-ERBB4 SIGNALING CONTROLS TWO STEPS IN THE REMODELING OF THE NEURAL CIRCUITS: PRUNING AND SYNAPSE FORMATION, THUS, BY MEANS OF CELL-SPECIFIC ABLATION IN VIVO, IN UTERO ELECTROPORATION AND INFECTION, FUNCTIONAL STUDIES IN PRIMARY CELL CULTURE AND HIGH THROUGHPUT SCREENING, WE PROPOSE TO ACCOMPLISH TWO FUNDAMENTAL GOALS: (1) TO DETERMINE WHETHER FAK IS A GENERAL PRUNING DIRECTOR IN VIVO AND TO UNDERSTAND SOME OF THE MECHANISMS BY WHICH FAK MEDIATES THOSE PRUNING EVENTS, (2) TO DETERMINE WHETHER NRG1-ERBB4 SIGNALING IS RESTRICTED PRESYNAPTICALLY TO THE CHANDELIER SYNAPSES, THE PRECISE CONTRIBUTION OF BOTH PRE- AND POST-SYNAPTIC ERBB4 FUNCTION AND TO INVESTIGATE SOME OF THE MECHANISMS BEHIND NRG1-ERBB4 SIGNALING IN THE FORMATION OF THESE SYNAPSES, SOME OF THE INSIGHTS OF THIS INVESTIGATION WILL PROBABLY BE APPLICABLE FOR UNDERSTANDING NOT JUST THE INITIAL DEVELOPMENT OF NEURAL CONNECTIONS BUT ALSO NORMAL PLASTIC REARRANGEMENTS OF NEURAL CONNECTIONS OCCURRING IN THE HEALTHY AND PATHOLOGIC BRAINS, PARTICULARLY IN THE SCHIZOPHRENIA,

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