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Title: Spindle-related phosphorylation of calcium-calmoduline kinase II in the rat hippocampus during REM sleep
Authors: Pereira, C. M.
Cota, V. R.
Dias, G.
Souza, A.
Ribeiro, Sidarta Tollendal Gomes
Santos, S.
Keywords: Sleep, memory, hippocampus, kinases, spindles
Issue Date: Aug-2011
Portuguese Abstract: Objectives: This work had two aims: 1) To investigate how the sleep-wake cycle affects the phosphorylation levels of Ca(2+)/calmodulin- dependent protein kinase II (CaMKII), which plays a key role in memory consolidation and Zif268/Arc transcription; and 2) to investigate the relationship between spindle features and CaMKII phosphorylation levels. Methods and Results: Young adult male rats (n=24) were implanted with electrodes for chronic recordings of local field potentials in the dentate gyrus and cerebral cortex, to identify WK, SWS and REM (J Neurosci 24(49): 11137-11147, 2004). Experimental animals were allowed to explore 4 novel objects introduced in the recording box for 10 minutes as previously described (PLoS Biol 2(1): E24, 2004), while controls were unexposed to novel stimuli. The animals were then kept awake for 3 hours, to avoid detecting CaMKII phosphorylation directly related to the exploration of novel objects. Animals were then allowed to sleep and were decapitated immediately after entering SWS (at least 10 minutes) or REM (at least 2 minutes). Animals in the WK group had an additional 10 minutes of sleep deprivation before killing. The brains were quickly removed and the left hemispheres were frozen for immuhistochemistry assays, while the right hemispheres were used for protein extraction and immunoblots. Global phosphorylation levels of CaMKIIα (Thr286) assessed in immunoblots revealed a significant decrease in CaMKIIα activation during REM in rats exposed to novel objects, in comparison to WK. As expected, no statistically significant differences occurred in controls. Immunohistochemistry used to investigate CaMKII activation in three specific hippocampal regions (dentate gyrus, CA3 and CA1) revealed significant differences in animals exposed to novel objects: CamKII phosphorylation decreased from WK to SWS in the hippocampal cell layers analyzed, but there was a significant increase from SWS to REM. Controls displayed no significant differences. Novel experience was concomitant in our dataset with an increase in spindle density, which was strongly correlated with CAMKII phosphorylation levels in the REM group, but not in the WK or SWS groups. Conclusions: Our results suggest that experience-dependent changes in the density of spindles during SWS and/or intermediate sleep before REM determine subsequent levels of CAMKII phosphorylation in local hippocampal circuits, when assessed immediately after REM. A similar relationship relates spindle power and Zif-268 mRNA expression 30 minutes after REM (Frontiers in Neuroscience 1: 43-55, 2007), suggesting a causal chain linking spindles, CAMKII phosphorylation and zif-268 expression.
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