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 (200µM), whereas NE and ACh effects were disrupted by ouabain (1µM) or iodoacetate (100µM). 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.
Highlights
Changes in extracellular potassium concentration ([K+]e) modulate neuronal networks via membrane depolarization/hyperpolarization with subsequent activation/inactivation of voltagegated channels and alteration of transmission at the synapse(Bellot-Saez, Kekesi, Morley, & Buskila, 2017; Kofuji & Newman, 2004; Larsen, Stoica, & MacAulay, 2016; Sibille, Dao Duc, Holcman, & Rouach, 2015; Sibille, Pannasch, & Rouach, 2014)
We demonstrate that the neuromodulators serotonin, norepinephrine, and acetylcholine all have distinct effects on astrocyte-mediated extracellular potassium regulation and that these differential actions are associated with the different effects of the neuromodulators on cortical networks
It is widely accepted that activity-induced changes in [K+]e are rapidly managed by the astrocytic potassium inward rectifying channel subtype 4.1 (Kir4.1)(Bellot-Saez et al, 2017; Butt & Kalsi, 2006; Chever, Djukic, McCarthy, & Amzica, 2010; D'Ambrosio, Gordon, & Winn, 2002; Larsen et al, 2014; Larsen & MacAulay, 2014; Sibille et al, 2015) and the astrocyte-specific α2β2 isoform of the Na+/K+-ATPase (NKA)(D'Ambrosio et al, 2002; Larsen et al, 2014; Pellerin & Magistretti, 1997; Stoica et al, 2017)
Summary
Changes in extracellular potassium concentration ([K+]e) modulate neuronal networks via membrane depolarization/hyperpolarization with subsequent activation/inactivation of voltagegated channels and alteration of transmission at the synapse(Bellot-Saez, Kekesi, Morley, & Buskila, 2017; Kofuji & Newman, 2004; Larsen, Stoica, & MacAulay, 2016; Sibille, Dao Duc, Holcman, & Rouach, 2015; Sibille, Pannasch, & Rouach, 2014). Due to the highly negative resting membrane potential of astrocytes, Kir4.1 is highly responsive to increases in [K+]e with local inward K+ uptake into astrocytes(Sibille et al, 2015; Sibille et al, 2014) whereas the astrocyte-specific NKA is responsive to changes in intracellular Na+ driven by the synapse-dependent glutamate transporter(Larsen, Holm, Vilsen, & MacAulay, 2016; Larsen, Stoica, et al, 2016; Pellerin & Magistretti, 1997) and/or the Na+/Ca2+ exchanger in response to astrocyte Ca2+ transients(Wang, Smith, et al, 2012). Any neurotransmitter or neuromodulator that can alter or regulate astrocytic Kir4.1 or NKA activity may have indirect influence on network activity/function via [K+]e
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