1. Neuroscience Graduate Group,
2. Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
3. Neuroscience and Molecular Pharmacology, Wolfson and Davidson Buildings, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
4. Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada

Correspondence to: Ted Abel² Correspondence and requests for materials should be addressed to T.A. (Email: abele@sas.upenn.edu).

Millions of people regularly obtain insufficient sleep¹. Given the effect 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 models that are dependent on the hippocampus^{2, 3, 4, 5}. Here we have identified a molecular mechanism by which brief sleep deprivation alters hippocampal function. Sleep deprivation selectively impaired 3', 5'-cyclic AMP (cAMP)- and protein kinase A (PKA)-dependent forms of synaptic plasticity⁶ in the mouse hippocampus, reduced cAMP signalling, and increased activity and protein levels of phosphodiesterase 4 (PDE4), an enzyme that degrades cAMP. Treatment of mice with phosphodiesterase inhibitors rescued the sleep-deprivation-induced deficits in cAMP signalling, synaptic plasticity and hippocampus-dependent memory. These findings demonstrate that brief sleep deprivation disrupts hippocampal function by interfering with cAMP signalling through increased PDE4 activity. Thus, drugs that enhance cAMP signalling may provide a new therapeutic approach to counteract the cognitive effects of sleep deprivation.

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