24 October 2009. The cognitive difficulties stemming from sleep deprivation may be reversible, according to a paper appearing in the October 22 issue of Nature. Researchers led by Ted Abel at the University of Pennsylvania pinpoint a molecular pathway that is altered by sleep deprivation in a way that disrupts both synaptic plasticity and memory formation in mice. Both effects could be reversed by rolipram, a drug that inhibits phosphodiesterase4 (PDE4), which normally degrades cAMP.
Although little is known about the causes or consequences of sleep disturbances in people with schizophrenia (Manoach and Stickgold, 2009), this basic science study does offer some unexpected links to the disorder, including the finding that certain PDE4 isoforms (though not the one implicated in this study) are binding partners of the schizophrenia susceptibility gene DISC1, and the suggestion that rolipram could be a candidate antipsychotic medication.
Led by first author Christopher Vecsey of the University of Pennsylvania, the team found that mice deprived of sleep for five hours lost some components of hippocampal long-term potentiation (LTP), the plasticity that normally strengthens synaptic connections between neurons and underlies some forms of memory. In their hippocampal slice recordings, the researchers found that this loss was specific to the two types of LTP that require a cAMP signaling pathway, suggesting that sleep deprivation altered the regulation of cAMP levels. Consistent with this, the researchers found that sleep deprivation lowered cAMP levels in the CA1 region of the hippocampus (as well as the downstream target CREB) and boosted the activity and protein levels of PDE4, an enzyme that degrades cAMP. Blocking this abnormally high PDE4 activity with the PDE4 inhibitor rolipram fully rescued LTP, with increases in synaptic strength similar to those observed in non-sleep deprived mice. These findings suggest that sleep deprivation raises the threshold for inducing these types of LTP.
These effects extended to context-specific memory formation, which relies on the hippocampus. To introduce a memory, mice receive a foot shock in a chamber in a single trial. When they are placed in the same chamber later, they freeze in fear, which is an assay for their memory for the chamber. When mice were sleep deprived after receiving the foot shock, they exhibited reduced freezing behavior; in contrast, those that received injections of rolipram after sleep deprivation had normal amounts of freezing, indicating a preserved memory for the chamber. These findings are in line with accumulating evidence for the need for sleep to consolidate memories (Walker, 2009), and show that inhibiting PDE4 may bypass this need at least temporarily.
These results are particularly tantalizing because rolipram (along with inhibitors of other PDEs) has been proposed as an antipsychotic drug, on the grounds that it might restore putatively abnormal cAMP levels in neurons by a mechanism other than the canonical dopamine D2 receptor-G protein cascade (for review, see Siuciak, 2008; Halene and Siegel, 2007). Another possible link to schizophrenia is the finding that the protein encoded by the disrupted-in-schizophrenia 1 (DISC1) gene normally binds to the PDE4B isoform, rendering it inactive (see SRF related news story). Any perturbations in DISC1 might leave PDE4B unbound and in overdrive. Also, polymorphisms in the genes for PDE4B and PDE4D have been associated with schizophrenia, and may alter PDE4 activity. As a PDE4-specific inhibitor, rolipram may normalize activity in this variety of PDE4 isoforms. The new findings highlight how a drug that targets an intracellular second messenger system involving cAMP, rather than a neurotransmitter receptor, might mitigate the cognitive difficulties resulting from sleep disturbances in healthy people, not to mention any such processes in people with schizophrenia.—Michele Solis.
Vecsey C, Baillie G, Jaganath D, Havekes R, Daniels A, Wimmer M, Huang T, Brown K, Li X, Descalzi G, Kim S, Chen T, Shang Y, Zhuo M, Houslay M, Abel T. Sleep deprivation impairs cAMP signalling in the hippocampus. Nature. 2009 Oct 22; 461:1122. Abstract