Sleep deprivation impairs cAMP signalling in the hippocampus

It is well known that sleep deprivation can have cognitive consequences, including learning and memory deficits, but the mechanisms by which sleep deprivation affects brain function remain unknown. New experiments identify the cyclic AMP pathway as a functional target of sleep deprivation, specifically the impairment of cAMP/PKA-based plasticity in the hippocampus. Rescuing cAMP signalling using phosphodiesterase inhibitors also rescues the memory deficits, pointing to cAMP/PKA signalling enhancers as a possible therapeutic approach to counteract the cognitive effects of lost sleep. Sleep deprivation can have adverse cognitive effects, with one of the major consequences on the brain being memory deficits in learning models that are dependent on the hippocampus. A molecular mechanism by which brief sleep deprivation alters hippocampal function is now identified in mice; it involves the impairment of cyclic-AMP- and protein-kinase-A-dependent forms of synaptic plasticity. 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 hippocampus2,3,4,5. 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.