Local extracellular K ⁺ in cortex regulates norepinephrine levels, network state, and behavioral output

Abstract

Extracellular potassium concentration ([K + ] e ) is known to increase as a function of arousal. [K + ] e is also a potent modulator of transmitter release. Yet, it is not known whether [K + ] e is involved in the neuromodulator release associated with behavioral transitions. We here show that manipulating [K + ] e controls the local release of monoaminergic neuromodulators, including norepinephrine (NE), serotonin, and dopamine. Imposing a [K + ] e increase is adequate to boost local NE levels, and conversely, lowering [K + ] e can attenuate local NE. Electroencephalography analysis and behavioral assays revealed that manipulation of cortical [K + ] e was sufficient to alter the sleep–wake cycle and behavior of mice. These observations point to the concept that NE levels in the cortex are not solely determined by subcortical release, but that local [K + ] e dynamics have a strong impact on cortical NE. Thus, cortical [K + ] e is an underappreciated regulator of behavioral transitions.

How astrocytic chloride modulates brain states

“…The ionic environment of the CNS is of fundamental importance for the function of the nervous tissue. [ 7,16 ] Even relatively minor changes in concentration of K + , Ca 2+ , Na + and Cl − profoundly affect action potential generation and neurotransmission, whereas loss of ionostasis triggers pathological processes. [ 17 ] Ionic composition of the CNS fluids is highly dynamic, with a concentration of major ions fluctuating within a wide margin: for example, Na + concentration in the cerebrospinal fluid varies between 140 mM and 180 mM over the 24 h cycle.…”

“…[ 20 ] Local changes of [K + ] o have furthermore been shown to regulate norepinephrine levels, network states and behavioural output. [ 16 ] Maintenance of CNS K + homeostasis is an archetypal function of astrocytes; astrocytic K + buffering was discovered in 1960s [ 21,22 ] and has been extensively studied since. In physiological context, local K + buffering is mainly supported by astrocyte‐specific α2‐subunit‐containing Na + ‐K + ATPase (NKA), which accumulates K + , and inward rectifier K ir 4.1 K + channels, which supply K + back to the extracellular space after the cessation of neuronal activity to restore neuronal ionic gradients.…”