Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance both memory and synaptic plasticity. The current model for the action of HDAC inhibitors assumes that they alter gene expression globally and thus affect memory processes in a nonspecific manner. Here, we show that the enhancement of hippocampus-dependent memory and hippocampal synaptic plasticity by HDAC inhibitors is mediated by the transcription factor cAMP response element-binding protein (CREB) and the recruitment of the transcriptional coactivator and histone acetyltransferase CREB-binding protein (CBP) via the CREB-binding domain of CBP. Furthermore, we show that the HDAC inhibitor trichostatin A does not globally alter gene expression but instead increases the expression of specific genes during memory consolidation. Our results suggest that HDAC inhibitors enhance memory processes by the activation of key genes regulated by the CREB:CBP transcriptional complex.

Millions of people regularly obtain insufficient sleep1. Given the impact of sleep deprivation on our lives, understanding the cellular and molecular pathways affected by sleep deprivation is clearly of social and clinical importance. One of the major effects of sleep deprivation on the brain is to produce memory deficits in learning paradigms that are dependent on the hippocampus2–5. In this study, we have identified a molecular mechanism by which brief sleep deprivation alters hippocampal function. Sleep deprivation selectively impaired cAMP/PKA-dependent forms of synaptic plasticity6 in the hippocampus, reduced cAMP signaling, and increased activity and protein levels of phosphodiesterase-4 (PDE4), an enzyme that degrades cAMP. Treatment with PDE inhibitors rescued the sleep deprivation-induced deficits in cAMP signaling, synaptic plasticity, and hippocampus-dependent memory. These findings demonstrate that brief sleep deprivation disrupts hippocampal function by interfering with cAMP signaling through increased PDE4 activity. Thus drugs that enhance cAMP signaling may provide a novel therapeutic approach to counteract the cognitive effects of sleep deprivation.

Sleep deprivation is a common problem of considerable health and economic impact in today's society. Sleep loss is associated with deleterious effects on cognitive functions such as memory and has a high comorbidity with many neurodegenerative and neuropsychiatric disorders. Therefore, it is crucial to understand the molecular basis of the effect of sleep deprivation in the brain. In this study, we combined genome-wide and traditional molecular biological approaches to determine the cellular and molecular impacts of sleep deprivation in the mouse hippocampus, a brain area crucial for many forms of memory. Microarray analysis examining the effects of 5 h of sleep deprivation on gene expression in the mouse hippocampus found 533 genes with altered expression. Bioinformatic analysis revealed that a prominent effect of sleep deprivation was to downregulate translation, potentially mediated through components of the insulin signaling pathway such as the mammalian target of rapamycin (mTOR), a key regulator of protein synthesis. Consistent with this analysis, sleep deprivation reduced levels of total and phosphorylated mTOR, and levels returned to baseline after 2.5 h of recovery sleep. Our findings represent the first genome-wide analysis of the effects of sleep deprivation on the mouse hippocampus, and they suggest that the detrimental effects of sleep deprivation may be mediated by reductions in protein synthesis via downregulation of mTOR. Because protein synthesis and mTOR activation are required for long-term memory formation, our study improves our understanding of the molecular mechanisms underlying the memory impairments induced by sleep deprivation.

Drosophila melanogaster has been used for decades in the study of circadian behavior, and more recently has become a popular model for the study of sleep. The classic method for monitoring fly activity involves counting the number of infrared beam crosses in individual small glass tubes. Incident recording methods such as this can measure gross locomotor activity, but they are unable to provide details about where the fly is located in space and do not detect small movements (i.e. anything less than half the enclosure size), which could lead to an overestimation of sleep and an inaccurate report of the behavior of the fly. This is especially problematic if the fly is awake, but is not moving distances that span the enclosure. Similarly, locomotor deficiencies could be incorrectly classified as sleep phenotypes. To address these issues, we have developed a locomotor tracking technique (the “Tracker” program) that records the exact location of a fly in real time. This allows for the detection of very small movements at any location within the tube. In addition to circadian locomotor activity, we are able to collect other information, such as distance, speed, food proximity, place preference, and multiple additional parameters that relate to sleep structure. Direct comparisons of incident recording and our motion tracking application using wild type and locomotor-deficient (CASK-β null) flies show that the increased temporal resolution in the data from the Tracker program can greatly affect the interpretation of the state of the fly. This is especially evident when a particular condition or genotype has strong effects on the behavior, and can provide a wealth of information previously unavailable to the investigator. The interaction of sleep with other behaviors can also be assessed directly in many cases with this method.

Sleep deprivation (SD) can have a negative impact on cognitive function, but the mechanism(s) by which SD modulates memory remain unclear. We have previously shown that astrocyte-derived adenosine is a candidate molecule involved in the cognitive deficits following a brief period of SD (Halassa et al., 2009). In this study, we examined whether genetic disruption of SNARE-dependent exocytosis in astrocytes (dnSNARE mice) or pharmacological blockade of A1 receptor signaling using an adenosine A1 receptor (A1R) antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT) could prevent the negative effects of 6 hours of SD on hippocampal late-phase long-term potentiation (L-LTP) and hippocampus-dependent spatial object recognition memory. We found that SD impaired L-LTP in wild-type mice but not in dnSNARE mice. Similarly, this deficit in L-LTP resulting from SD was prevented by a chronic infusion of CPT. Consistent with these results, we found that hippocampus-dependent memory deficits produced by SD were rescued in dnSNARE mice and CPT-treated mice. These data provide the first evidence that astrocytic ATP and adenosine A1R activity contribute to the effects of SD on hippocampal synaptic plasticity and hippocampus-dependent memory, and suggest a new therapeutic target to reverse the hippocampus-related cognitive deficits induced by sleep loss.