Chronic enhancement of CREB activity in the hippocampus interferes with the retrieval of spatial information

Abstract

The activation of cAMP-responsive element-binding protein (CREB)-dependent gene expression is thought to be critical for the formation of different types of long-term memory. To explore the consequences of chronic enhancement of CREB function on spatial memory in mammals, we examined spatial navigation in bitransgenic mice that express in a regulated and restricted manner a constitutively active form of CREB, VP16-CREB, in forebrain neurons. We found that chronic enhancement of CREB activity delayed the acquisition of an allocentric strategy to solve the hidden platform task. The ability to turn on and off transgene expression allowed us to dissect the role of CREB in dissociable memory processes. In mice in which transgene expression was turned on during memory acquisition, turning off the transgene reestablished the access to the memory trace, whereas in mice in which transgene expression was turned off during acquisition, turning on the transgene impaired memory expression in a reversible manner, indicating that CREB enhancement specifically interfered with the retrieval of spatial information. The defects on spatial navigation in mice with chronic enhancement of CREB function were not corrected by conditions that increased further CREB-dependent activation of hippocampal memory systems, such as housing in an enriched environment. These results along with previous findings in CREB-deficient mutants indicate that the relationship of CREB-mediated plasticity to spatial memory is an inverted-U function, and that optimal learning in the water maze requires accurate regulation of this pathway.

cAMP Response Element-Binding Protein Is a Primary Hub of Activity-Driven Neuronal Gene Expression

“…4 A), which represents a valuable positive control. Among the candidate genes for differential promoter/exon usage, we found Bdnf, a gene with multiple internal promoters (Aid et al, 2007) for which we confirmed the preferential usage of promoter I over promoter IV by caCREB (Barco et al, 2005;Viosca et al, 2009) (Fig. 4 B).…”

Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP 3 R) Ca 2+ signaling

“…The effects of CREB depend on its level and the duration of activation, as well as on the developmental stages of specific brain regions (25,47). Chronic CREB activation leads to memory deficits (48), cognitive decline (49), interference with information retrieval (48), and neurodegeneration (50). It is possible that the constitutive CREB activation caused by FAD PS expression reported here could contribute to the premature cognitive deficits normally associated with aging.…”

Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome

“…Indeed, CREB-dependent transcription is induced following an array of learning paradigms and is required for normal cognitive function (Impey et al 1998;Mizuno et al 2002;Porte et al 2008). Nevertheless, while moderate increases in CREB activity facilitate learning, chronic enhancement of CREB-dependent transcription impairs cognitive capacity, paralleling the learning phenotypes observed in tTA::miR-132 animals (Viosca et al 2009;Hansen et al 2013). Here, we present the 18 genes that are significantly increased in CaMKII-Cre::miR-132/-212 f/f animals, decreased in tTA::miR-132 animals, and that appear as informatically predicted targets of miR-132.…”