Serotonin, norepinephrine, and acetylcholine differentially affect astrocytic potassium clearance to modulate somatosensory signaling in male mice

Changes in extracellular potassium ([K⁺ ]_e ) modulate neuronal networks via changes in membrane potential, voltage-gated channel activity, and alteration to transmission at the synapse. Given the limited extracellular space in the central nervous system, potassium clearance is crucial. As activity-induced potassium transients are rapidly managed by astrocytic Kir4.1 and astrocyte-specific Na⁺ /K⁺ -ATPase, any neurotransmitter/neuromodulator that can regulate their function may have indirect influence on network activity. Neuromodulators differentially affect cortical/thalamic networks to align sensory processing with differing behavioral states. Given serotonin (5HT), norepinephrine (NE), and acetylcholine (ACh) differentially affect spike frequency adaptation and signal fidelity ("signal-to-noise") in somatosensory cortex, we hypothesize that [K⁺ ]_e may be differentially regulated by the different neuromodulators to exert their individual effects on network function. This study aimed to compare effects of individually applied 5HT, NE, and ACh on regulating [K⁺ ]_e in connection to effects on cortical-evoked response amplitude and adaptation in male mice. Using extracellular field and K⁺ ion-selective recordings of somatosensory stimulation, we found that differential effects of 5HT, NE, and ACh on [K⁺ ]_e regulation mirrored differential effects on amplitude and adaptation. 5HT effects on transient K⁺ recovery, adaptation, and field post-synaptic potential amplitude were disrupted by barium (200 µM), whereas NE and ACh effects were disrupted by ouabain (1 µM) or iodoacetate (100 µM). Considering the impact [K⁺ ]_e can have on many network functions; it seems highly efficient that neuromodulators regulate [K⁺ ]_e to exert their many effects. This study provides functional significance for astrocyte-mediated buffering of [K⁺ ]_e in neuromodulator-mediated shaping of cortical network activity.