title: CRTC1 Function During Memory Encoding Is Disrupted in Neurodegeneration.
abstract: Associative memory impairment is an early clinical feature of dementia patients, but the molecular and cellular mechanisms underlying these deficits are largely unknown. In this study, we investigated the functional regulation of the cyclic adenosine monophosphate response element binding protein (CREB)-regulated transcription coactivator 1 (CRTC1) by associative learning in physiological and neurodegenerative conditions.
  
  
  
  We evaluated the activation of CRTC1 in the hippocampus of control mice and mice lacking the Alzheimer's disease-linked presenilin genes (presenilin conditional double knockout [PS cDKO]) after one-trial contextual fear conditioning by using biochemical, immunohistochemical, and gene expression analyses. PS cDKO mice display classical features of neurodegeneration occurring in Alzheimer's disease including age-dependent cortical atrophy, neuron loss, dendritic degeneration, and memory deficits.
  
  
  
  Context-associative learning, but not single context or unconditioned stimuli, induces rapid dephosphorylation (Ser151) and translocation of CRTC1 from the cytosol/dendrites to the nucleus of hippocampal neurons in the mouse brain. Accordingly, context-associative learning induces differential CRTC1-dependent transcription of c-fos and the nuclear receptor subfamily 4 (Nr4a) genes Nr4a1-3 in the hippocampus through a mechanism that involves CRTC1 recruitment to CRE promoters. Deregulation of CRTC1 dephosphorylation, nuclear translocation, and transcriptional function are associated with long-term contextual memory deficits in PS cDKO mice. Importantly, CRTC1 gene therapy in the hippocampus ameliorates context memory and transcriptional deficits and dendritic degeneration despite ongoing cortical degeneration in this neurodegeneration mouse model.
  
  
  
  These findings reveal a critical role of CRTC1 in the hippocampus during associative memory, and provide evidence that CRTC1 deregulation underlies memory deficits during neurodegeneration.
authors: Institut de Neurociències, Department de Bioquímica i Biologia Molecular; and the; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Arnaldo
authors: A
authors: Parra-Damas
authors: Institut de Neurociències, Department de Bioquímica i Biologia Molecular; and the; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Meng
authors: M
authors: Chen
authors: Institut de Neurociències, Department de Bioquímica i Biologia Molecular; and the; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Lilian
authors: L
authors: Enriquez-Barreto
authors: Institut de Neurociències, Department de Bioquímica i Biologia Molecular; and the.
authors: Laura
authors: L
authors: Ortega
authors: Institut de Neurociències, Department de Bioquímica i Biologia Molecular; and the.
authors: Sara
authors: S
authors: Acosta
authors: Institut de Neurociències, Department de Bioquímica i Biologia Molecular; and the.
authors: Judith Camats
authors: JC
authors: Perna
authors: Institut de Neurociències, Department de Bioquímica i Biologia Molecular; and the.
authors: M Neus
authors: MN
authors: Fullana
authors: Institut de Neurociències, Department de Bioquímica i Biologia Molecular; and the; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: José
authors: J
authors: Aguilera
authors: Institut de Neurociències, Department de Bioquímica i Biologia Molecular; and the; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: José
authors: J
authors: Rodríguez-Alvarez
authors: Institut de Neurociències, Department de Bioquímica i Biologia Molecular; and the; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address: carlos.saura@uab.es.
authors: Carlos A
authors: CA
authors: Saura
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000523:psychology*; D000818:Animals; D001245:Association Learning / Q000502:physiology; D003214:Conditioning, Classical / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003712:Dendrites / Q000473:pathology; D005239:Fear / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D053764:Presenilin-1 / Q000235:genetics; D053766:Presenilin-2 / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C492004:Creb1 protein, mouse; C519509:Crtc1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D053764:Presenilin-1; D053766:Presenilin-2; C095101:Psen2 protein, mouse; D014157:Transcription Factors; C580804:presenilin 1, mouse
keywords: Alzheimer’s disease; CREB; Gene therapy; Memory; Neurodegeneration; TORC