Role of the transcriptional coactivator crtc1 in hippocampal-dependent associative memory

• Autores: Meng Chen
• Directores de la Tesis: Carlos A. Saura Antolín (dir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2014
• Idioma: inglés
• Tribunal Calificador de la Tesis: José Aguilera Avila (presid.), Jorge Valero Gómez-Lobo (secret.), Carles Sindreu (voc.)
• Enlaces
  • Tesis en acceso abierto en:  TDX  DDD 
• Resumen

  • Alzheimer¿s disease (AD) is an age-dependent neurodegenerative disorder and the main cause of dementia in the elderly. Cognitive decline in AD correlates with synaptic dysfunction and neuron loss. Besides the classical episodic memory impairment symptoms, dementia patients develop deficits in encoding and retrieval of emotional associative memory and fear conditioning. The cAMP-response element binding protein (CREB) signaling pathway regulates gene expression programs mediating synaptic plasticity and memory. Recent evidences suggest that deregulation of cAMP/Ca2+-mediated CREB signaling negatively affect hippocampal synaptic plasticity, memory and synapse loss in AD models.

    In this doctoral thesis, we investigated the specific role of the CREB transcriptional coactivator Crtc1 in associative memory in physiological and pathological conditions. By using fear conditioning, we found that context conditioning induces rapid translocation of Crtc1 from the cytosol to the nucleus of neurons in the CA1 and CA3 regions of the adult mouse hippocampus. Crtc1 nuclear translocation is associated with Crtc1 dephosphorylation, whereas Creb phosphorylation is induced independently of a paired unconditioned stimulus. Interestingly, Crtc1 dephosphorylation is induced specifically in the hippocampus by context conditioning but not by context encoding or shock stimuli. Contextual conditioning but not context encoding or shock up regulates gene epression levels in a Crtc1-dependent manner. Notably, reduced Crtc1 nuclear translocation and Crtc1-dependent transcription is associated with long-term contextual memory impairments in a mouse model of neurodegeneration lacking the presenilin genes (PS cDKO). In addition, adeno-associated viral-Crtc1 gene transfer in the hippocampus reverses hippocampal Crtc1-dependent transcription changes and associative memory deficits. Finally, post mortem analysis shows that CRTC1 levels are reduced in human hippocampus at intermediate Braak III/IV pathological stages. These findings reveal a critical role of Crtc1 nuclear translocation and transcriptional function in contextual memory encoding in physiological and neurodegenerative conditions.