Arnaldo Parra-Damas1, Meng Chen1, Lilian Enriquez-Barreto1, Laura Ortega2, Sara Acosta2, Judith Camats Perna2, M Neus Fullana2, José Aguilera1, José Rodríguez-Alvarez1, Carlos A Saura3. 1. 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. 2. Institut de Neurociències, Department de Bioquímica i Biologia Molecular; and the. 3. 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.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: Associative memory impairment is an early clinical feature of dementiapatients, 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. METHODS: 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. RESULTS: 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 neurodegenerationmouse model. CONCLUSIONS: 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: Devin Wahl; Sean Cp Coogan; Samantha M Solon-Biet; Rafael de Cabo; James B Haran; David Raubenheimer; Victoria C Cogger; Mark P Mattson; Stephen J Simpson; David G Le Couteur Journal: Clin Interv Aging Date: 2017-09-08 Impact factor: 4.458
Authors: E N Wilson; S Do Carmo; M F Iulita; H Hall; A Ducatenzeiler; A R Marks; S Allard; D T Jia; J Windheim; A C Cuello Journal: Transl Psychiatry Date: 2017-08-01 Impact factor: 6.222