The CBP KIX domain regulates long-term memory and circadian activity

Snehajyoti Chatterjee,Ted Abel,Shane G Poplawski,Joshua D Hawk,Jean-Christophe Cassel,Lisa C Lyons,Ethan Bahl,Jacob J Michaelson,Manish Yadav,Anne-Laurence Boutillier,Giulia S Porcari,Marie E Gaine,Anne Schneider-Anthony,Christopher C Angelakos,K Peter Giese

doi:10.1186/s12915-020-00886-1

Abstract

BackgroundCREB-dependent transcription necessary for long-term memory is driven by interactions with CREB-binding 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 phospho-CREB (Ser133) binding.ResultsWe found that CBPKIX/KIX mice were impaired in long-term memory, but not learning acquisition or short-term 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 free-running 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.ConclusionsThese 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.Graphical abstract

Highlights

cyclic-AMP response element-binding protein (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
To further characterize the specific role of the KIX domain in hippocampus-dependent longterm memory, we analyzed the consequences of a CBP KIX domain mutation on short- and long-term spatial memory using the Morris water maze (MWM), a hippocampus-dependent task
Assessment of the average swim speed during the training days revealed a small, albeit significant, difference in the swim speed in CBPKIX/KIX mice, raising the possibility that swim speed accounts for the difference in escape latencies. We find this possibility to be unlikely given the small difference in swim speed and the fact that we observed no significant difference between the WT and CBPKIX/KIX mice during the 1-h shortterm memory recall test suggesting swim speed was not a factor in the probe test. (Additional file 1: Fig. S1b)

Summary

Introduction

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. 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. Phosphorylation and activation of the cyclic-AMP response element-binding protein (CREB) is fundamental for the induction of gene transcription during long-term memory consolidation [1,2,3]. By 2050, adults 65 and older are predicted to comprise 16% of the world’s population, more than 1.5 billion individuals [9] For neurodegenerative diseases such as Alzheimer’s disease, individuals frequently experience mild cognitive impairments and memory issues years prior to disease diagnosis. Given that increased longevity increases the individual risk and societal economic burden of age-related diseases [10], there is a crucial need to understand the mechanisms and processes involved in long-term memory consolidation

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