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

Abstract

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.

Astrocytes—The Ultimate Effectors of Long-Range Neuromodulatory Networks?

“…In addition to effects on excitation-inhibition balance and gain modulation, [K + ] e affects frequency transmission and brain state. In our most recent study, we found that decreasing perfusate [K + ] reduced somatosensory adaptation similar to 5HT and NE (Wotton et al, 2020). During the repetitive firing of action potentials, [K + ] e increases at the synapse with each subsequent stimulation (Figure 2A).…”

“…The most likely scenario to account for the reduction in EPSP amplitude would be that the depolarization of the pre-synaptic terminal, as the [K + ] e rises, and slowing of sodium channel recovery from inactivation (Meeks and Mennerick, 2004) leads to a reduction in action potential amplitude, decrease in voltagegated calcium channel opening and reduced neurotransmitter release ( Figure 2B). Accordingly, in the low [K + ] e perfusate, K + does not accumulate to the same extent and less frequency adaptation is evident mimicking 5HT-and NE-mediated effects on K + clearance (Wotton et al, 2020). In light of this, the regulation of activity-dependent [K + ] e increases via both passive and active astrocyte uptake mechanisms enables rapid and precise control over somatosensory frequency transmission.…”

“…Using this computational model they showed that, although changes from sleep to wakefulness required inhibition of calcium-sensitive potassium channels with changes in extracellular ions only affecting the threshold, the transition from quiet to active wakefulness was mediated by a subtle change in extracellular ions; K + being the most potent (Rasmussen et al, 2017). Furthermore, given the known ability for neuromodulators to inhibit the calcium-sensitive K + channel (McCormick and Williamson, 1989;McCormick et al, 1993) and affect baseline [K + ] e (Ding et al, 2016;Wotton et al, 2020), it is reasonable that an increase in tonic neuromodulator release and effects on calcium-sensitive K + channels induces general wakefulness whereas phasic neuromodulator release with associated effects on extracellular ion concentrations governs transitions between quiet and active wakefulness.…”

“…The second involves an astrocyte calcium-mediated increase in [Na + ] via the Na + /Ca 2+ exchanger (Wang et al, 2012b) that may or may not depend on neural activity. Finally, the third involves direct long-range neuromodulator-mediated regulation of Na + /K + ATPase or Kir4.1 independent of local network activity (Wotton et al, 2020). Such diversity over the control of [K + ] e regulation that may or may not depend on local synaptic activity enables a powerful means to regulate brain-wide network connectivity and, ultimately, behavior.…”

“…Although a cocktail of neuromodulators (NE, ACh, DA, orexin, and HA) induced an increase in [K + ] e that was associated with the transition in brain state (Ding et al, 2016), recent evidence suggests that individual neuromodulators have differential effects (Wotton et al, 2020). 5HT, NE, and ACh differentially affected inward rectifiers and the Na + /K + ATPase to exert distinct effects on baseline [K + ] e as well as recovery from evoked K + increases that were associated with FIGURE 6 | Differential effects of neuromodulators on evoked increases in extracellular potassium mirror differential neuromodulator effects on adaptation.…”