CREB overexpression in dorsal CA1 ameliorates long-term memory deficits in aged rats

Abstract

The molecular mechanisms underlying age-related cognitive deficits are not yet fully elucidated. In aged animals, a decrease in the intrinsic excitability of CA1 pyramidal neurons is believed to contribute to age-related cognitive impairments. Increasing activity of the transcription factor cAMP response element-binding protein (CREB) in young adult rodents facilitates cognition, and increases intrinsic excitability. However, it has yet to be tested if increasing CREB expression also ameliorates age-related behavioral and biophysical deficits. To test this hypothesis, we virally overexpressed CREB in CA1 of dorsal hippocampus. Rats received CREB or control virus, before undergoing water maze training. CREB overexpression in aged animals ameliorated the long-term memory deficits observed in control animals. Concurrently, cells overexpressing CREB in aged animals had reduced post-burst afterhyperpolarizations, indicative of increased intrinsic excitability. These results identify CREB modulation as a potential therapy to treat age-related cognitive decline.DOI: http://dx.doi.org/10.7554/eLife.19358.001

Neuronal O-GlcNAcylation Improves Cognitive Function in the Aged Mouse Brain

“…We profiled hippocampal lysates from young and aged wild-type mice and observed a decrease in OGT protein levels, as well as a decrease in global protein O-GlcNAcylation with age ( Figures 1A and 1B). Next, we established a reference point for characteristic hallmarks of hippocampal aging reported to be amenable to brain rejuvenation [26][27][28][29]. First, we assessed the levels of the activated phosphorylated form of the transcription factor CREB (pCREB)-previously demonstrated to underlie improvements in hippocampal-dependent cognitive function in the aged brain [26,29], and whose O-GlcNAcylation status regulates amygdala-dependent memory formation [16].…”

“…Next, we established a reference point for characteristic hallmarks of hippocampal aging reported to be amenable to brain rejuvenation [26][27][28][29]. First, we assessed the levels of the activated phosphorylated form of the transcription factor CREB (pCREB)-previously demonstrated to underlie improvements in hippocampal-dependent cognitive function in the aged brain [26,29], and whose O-GlcNAcylation status regulates amygdala-dependent memory formation [16]. We detected an agedependent decrease in pCREB ( Figures 1C and 1D) concomitant with decreased expression of cFos ( Figures 1C and 1E), an immediate early gene downstream of CREB also implicated in cognitive rejuvenation [28].…”

Mimicking Age-Associated Gadd45γ Dysregulation Results in Memory Impairments in Young Adult Mice

“…The transcription factors cAMP response element-binding protein (CREB) and activating protein 1 (AP-1) are required for plasticity and memory (Alberini, 2009). Ageassociated changes in CREB activity and expression have been reported, and there is compelling evidence indicating that upregulation of CREB levels or activity ameliorates age-related memory deficits (Bach et al, 1999;Yu et al, 2017b). Recently, comparison of the hippocampal transcriptome of young adult and aged mice revealed that AP-1-associated gene expression is also affected during aging (Stilling et al, 2014).…”

The aged hematopoietic system promotes hippocampal‐dependent cognitive decline

“…We next investigated whether exposure to an aged hematopoietic system elicits synaptic changes in the hippocampus at a molecular and structural level. Activation of the transcription factor, CREB, via phosphorylation, has been implicated in age‐related cognitive decline and rejuvenation (Villeda et al, 2014; Yu, Curlik, Oh, Yin, & Disterhoft, 2017). Correspondingly, we assessed the levels of CREB phosphorylation (pCreb) and observed a decrease in Het HSC‐reconstituted young mice compared with Iso controls (Figure 1f,g).…”