Lack of sufficient sleep causes loss of efficiency in brain mechanisms of memory and learning, but exactly what goes wrong has been unclear. Vecsey et al. studied long-term potentiation (LTP) (a form of synaptic plasticity that serves as a model for memory formation) in hippocampal slices from mice that had slept as they wished or had been deprived of sleep for 5 hours. They observed that forms of LTP that depend on signaling through adenosine 3′-5′ monophosphate (cAMP) and protein kinase A (PKA) were diminished in hippocampal neurons from sleep-deprived animals, whereas other forms of LTP were not affected. They also confirmed that amounts of cAMP and phosphorylation of PKA substrates were both reduced in the neurons of sleep-deprived animals. These alterations appeared to result from increased activity of phosphodiesterase 4 (PDE4) (an enzyme that degrades cAMP). Pharmacological inhibition of PDE4 restored normal LTP in brain slices from sleep-deprived animals. These in vitro studies were also extended to experiments on behavior of whole animals. Mice that were deprived of sleep for 5 hours after a conditioning experience showed decreased context-specific memory when tested one or two days after conditioning. Impressively, treatment of the sleep-deprived animals with an inhibitor of PDE4 during the period of sleep deprivation prevented the loss of memory of the training experience. The authors propose that therapeutic manipulation of PDE4 activity might be useful in fending off cognitive defects in bleary-eyed humans.
C. G. Vecsey, G. S. Baillie, D. Jaganath, R. Havekes, A. Daniels, M. Wimmer, T. Huang, K. M. Brown, X.-Y. Li, G. Descalzi, S. S. Kim, T. Chen, Y.-Z. Shang, M. Zhou, M. D. Houslay, T. Abel. Sleep deprivation impairs cAMP signalling in the hippocampus. Nature 461, 1122–1125 (2009). [PubMed]