期刊
JOURNAL OF NEUROSCIENCE
卷 30, 期 28, 页码 9402-9410出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2154-10.2010
关键词
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资金
- Ministerio de Ciencia e Innovacion [SAF2007-64115, CIBERNED CB06/05/0042]
- Ministerio de Sanidad [FIS 04/0937, FIS 07/1137]
- European Commission [200611]
Activity-dependent gene expression mediating changes of synaptic efficacy is important for memory storage, but the mechanisms underlying gene transcriptional changes in age-related memory disorders are poorly understood. In this study, we report that gene transcription mediated by the cAMP-response element binding protein (CREB)-regulated transcription coactivator CRTC1 is impaired in neurons and brain from an Alzheimer's disease (A beta) transgenic mouse expressing the human beta-amyloid precursor protein (APP(Sw,Ind)). Suppression of CRTC1-dependent gene transcription by beta-amyloid (A beta) in response to cAMP and Ca2+ signals is mediated by reduced calcium influx and disruption of PP2B/calcineurin-dependentCRTC1dephosphorylation at Ser151. Consistently, expression of CRTC1 or active CRTC1 S151A and calcineurin mutants reverse the deficits on CRTC1 transcriptional activity in APPSw, Ind neurons. Inhibition of calcium influx by pharmacological blockade of L-type voltage-gated calcium channels (VGCCs), but not by blocking NMDA or AMPA receptors, mimics the decrease on CRTC1 transcriptional activity observed in APP(Sw,Ind) neurons, whereas agonists of L-type VGCCs reverse efficiently these deficits. Consistent with a role of CRTC1 on A beta-induced synaptic and memory dysfunction, we demonstrate a selective reduction of CRTC1-dependent genes related to memory (Bdnf, c-fos, and Nr4a2) coinciding with hippocampal-dependent spatial memory deficits in APP(Sw,Ind) mice. These findings suggest that CRTC1 plays a key role in coupling synaptic activity to gene transcription required for hippocampal-dependent memory, and that A beta could disrupt cognition by affecting CRTC1 function.
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