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 [Ca²⁺]_e, [Mg²⁺]_e, [H⁺]_e, and the extracellular volume. Opposite, natural sleep and anesthesia reduced [K⁺]_e while increasing [Ca²⁺]_e, [Mg²⁺]_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.