Changes in the composition of brain interstitial ions control the sleep-wake cycle

Wakefulness is driven by the widespread release of neuromodulators by the ascending arousal system. Yet, it is unclear how these substances orchestrate state-dependent, global changes in neuronal activity. Here, we show that neuromodulators induce increases in the extracellular K(+) concentration (K(+)e) in cortical slices electrically silenced by tetrodotoxin. In vivo, arousal was linked to AMPA receptor-independent elevations of K(+)e concomitant with decreases in Ca(2+)e, Mg(2+)e, H(+)e, and the extracellular volume. Opposite, natural sleep and anesthesia reduced K(+)e while increasing Ca(2+)e, Mg(2+)e, and H(+)e as well as the extracellular volume. Local cortical activity of sleeping mice could be readily converted to the stereotypical electroencephalography pattern of wakefulness by simply imposing a change in the extracellular ion composition. Thus, extracellular ions control the state-dependent patterns of neural activity.