Abstract
The activity-regulated cytoskeleton associated protein Arc is strongly and quickly upregulated by neuronal activity, synaptic potentiation and learning. Arc entry in the synapse is followed by the endocytosis of glutamatergic AMPA receptors (AMPARs), and its nuclear accumulation has been shown in vitro to result in a small decline in the transcription of the GluA1 subunit of AMPARs. Since these effects result in a decline in synaptic strength, we asked whether a change in Arc dynamics may temporally correlate with sleep-dependent GluA1 down-regulation. We measured the ratio of nuclear to cytoplasmic Arc expression (Arc Nuc/Cyto) in the cerebral cortex of EGFP-Arc transgenic mice that were awake most of the night and then perfused immediately before lights on (W mice), or were awake most of the night and then allowed to sleep (S mice) or sleep deprived (SD mice) for the first 2 h of the light phase. In primary motor cortex (M1), neurons with high levels of nuclear Arc (High Arc cells) were present in all mice, but in these cells Arc Nuc/Cyto was higher in S mice than in W mice and, importantly, ~15% higher in S mice than in SD mice collected at the same time of day, ruling out circadian effects. Greater Arc Nuc/Cyto with sleep was observed in the superficial layers of M1, but not in the deep layers. In High Arc cells, Arc Nuc/Cyto was also ~15%–30% higher in S mice than in W and SD mice in the superficial layers of primary somatosensory cortex (S1) and cingulate cortex area 1 (Cg1). In High Arc Cells of Cg1, Arc Nuc/Cyto and cytoplasmic levels of GluA1 immunoreactivities in the soma were also negatively correlated, independent of behavioral state. Thus, Arc moves to the nucleus during both sleep and wake, but its nuclear to cytoplasmic ratio increases with sleep in the superficial layers of several cortical areas. It remains to be determined whether the relative increase in nuclear Arc contributes significantly to the overall decline in the strength of excitatory synapses that occurs during sleep. Similarly, it remains to be determined whether the entry of Arc into specific synapses is gated by sleep.
Highlights
The immediate early gene Arc is strongly and quickly upregulated in excitatory glutamatergic neurons when synaptic activity increases, for instance during seizures, as well as after exploration of a novel environment or performance in many learning tasks (Link et al, 1995; Lyford et al, 1995; Guzowski et al, 1999, 2001; Vazdarjanova et al, 2006)
We confirmed in pilot experiments that in these mice, EGFP-Arc was widely expressed throughout the cerebral cortex, hippocampus and striatum after wake, and originally expressed EGFP-Arc was almost completely absent after 8 h of sleep, consistent with prior results shown in rats (Cirelli and Tononi, 2000)
In this study we found that Arc moves to the nucleus during both sleep and wake, but its nuclear to cytoplasmic ratio increases with sleep in the superficial layers of several cortical areas
Summary
The immediate early gene Arc (activity-regulated cytoskeletal protein, known as Arg3.1) is strongly and quickly upregulated in excitatory glutamatergic neurons when synaptic activity increases, for instance during seizures, as well as after exploration of a novel environment or performance in many learning tasks (Link et al, 1995; Lyford et al, 1995; Guzowski et al, 1999, 2001; Vazdarjanova et al, 2006). In many brain regions overtraining results in weaker Arc induction than new training (Kelly and Deadwyler, 2003), and in the hippocampus repeated presentation of the same stimulus leads to Arc reactivation in a progressively smaller neuronal population, despite no major changes in firing rates (Guzowski et al, 2006; Wang et al, 2006). Overall, these results indicate that Arc expression and neuronal activity are strongly coupled but the link is complex, because the levels of Arc reflect neuronal plasticity and novelty
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