The CBP KIX domain regulates long-term memory and circadian activity
- PDF / 3,680,303 Bytes
- 23 Pages / 595.276 x 790.866 pts Page_size
- 108 Downloads / 146 Views
RESEARCH ARTICLE
Open Access
The CBP KIX domain regulates long-term memory and circadian activity Snehajyoti Chatterjee1,2,3†, Christopher C. Angelakos4,5†, Ethan Bahl6,7, Joshua D. Hawk4,5, Marie E. Gaine3, Shane G. Poplawski4,5,8, Anne Schneider-Anthony1,2, Manish Yadav3, Giulia S. Porcari5, Jean-Christophe Cassel1, K. Peter Giese9, Jacob J. Michaelson6,10,11,12, Lisa C. Lyons3,13, Anne-Laurence Boutillier1,2* and Ted Abel3*
Abstract Background: CREB-dependent transcription necessary for long-term memory is driven by interactions with CREBbinding protein (CBP), a multi-domain protein that binds numerous transcription factors potentially affecting expression of thousands of genes. Identifying specific domain functions for multi-domain proteins is essential to understand processes such as cognitive function and circadian clocks. We investigated the function of the CBP KIX domain in hippocampal memory and gene expression using CBPKIX/KIX mice with mutations that prevent phosphoCREB (Ser133) binding. Results: We found that CBPKIX/KIX mice were impaired in long-term memory, but not learning acquisition or shortterm memory for the Morris water maze. Using an unbiased analysis of gene expression in the dorsal hippocampus after training in the Morris water maze or contextual fear conditioning, we discovered dysregulation of CREB, CLOCK, and BMAL1 target genes and downregulation of circadian genes in CBPKIX/KIX mice. Given our finding that the CBP KIX domain was important for transcription of circadian genes, we profiled circadian activity and phase resetting in CBPKIX/KIX mice. CBPKIX/KIX mice exhibited delayed activity peaks after light offset and longer freerunning periods in constant dark. Interestingly, CBPKIX/KIX mice displayed phase delays and advances in response to photic stimulation comparable to wildtype littermates. Thus, this work delineates site-specific regulation of the circadian clock by a multi-domain protein. Conclusions: These studies provide insight into the significance of the CBP KIX domain by defining targets of CBP transcriptional co-activation in memory and the role of the CBP KIX domain in vivo on circadian rhythms. Keywords: CBP KIX domain, Spatial memory, Hippocampus, Circadian rhythm
* Correspondence: [email protected]; [email protected] † Snehajyoti Chatterjee and Christopher C. Angelakos contributed equally to this work. 1 Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Université de Strasbourg, Strasbourg, France 3 Department of Neuroscience and Pharmacology, Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and
Data Loading...
