Sleep deprivation impairs cAMP signalling in the hippocampus

Abstract

Millions of people regularly obtain insufficient sleep. 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. 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 plasticity 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.

Figure 1. Brief sleep deprivation specifically impairs forms of LTP that depend on the cAMP/PKA pathway

(a) The maintenance of spaced 4-train LTP was significantly disrupted in slices from sleep-deprived mice (p=0.03). (b) A similar deficit was observed in LTP induced by theta-burst stimulation (TBS) (p=0.003). (c) Massed 4-train LTP was unaffected in hippocampal slices from sleep-deprived mice (p=0.67). (d) 1-train LTP was unaffected in hippocampal slices from sleep-deprived mice (p=0.97).

Figure 2. Phosphodiesterase (PDE) inhibition rescues impairments in forskolin-induced cAMP levels and LTP produced by brief sleep deprivation

(a) LTP induced by the adenylate cyclase activator forskolin (FSK) was impaired in sleep-deprived mice (SD) relative to controls (NSD) (p=0.007). (b) LTP induced by co-treatment with FSK and the PDE inhibitor IBMX was unaffected by sleep deprivation (p=0.48). (c) Sleep deprivation decreased baseline cAMP levels in CA1 regions of vehicle-treated slices (p=0.02) and significantly reduced FSK-induced cAMP levels (p=0.04). Co-application of FSK and IBMX resulted in similar cAMP levels in CA1 regions from SD and NSD mice (p=0.82).

Figure 3. Sleep deprivation increases PDE4 activity and gene expression in the hippocampus

(a) PDE4 activity was significantly upregulated in hippocampi from SD mice compared with NSD mice (p=0.039). (b) The PDE4 isoform PDE4A5 was significantly upregulated by sleep deprivation in the hippocampus (p=0.033). A sample blot is shown, with the nearest size markers indicated with arrows.

Figure 4. The PDE4 inhibitor rolipram rescues LTP and memory deficits caused by sleep deprivation

(a) Rolipram (ROL) treatment rescued deficits in spaced 4-train LTP due to sleep deprivation (p=0.003). (b) However, rolipram showed no further enhancement of spaced 4-train LTP in NSD mice (p=1.0). The black bar in (a) and (b) represents the time of ROL treatment. (c) Sleep deprivation significantly impaired context-specific memory (p=0.02), and treatment with rolipram rescued this deficit (p=0.0009) without affecting memory in non-sleep-deprived mice (p=0.99).