Astrocytic Potassium Clearance Research Articles

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 (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.

Neuro-Glial Network Model Of Postictal Generalized EEG Suppression (PGES).

Over the past couple of decades, glial cells have been highlighted as active agents in hyperexcitability of neuronal networks, specifically playing key roles in seizure onset and termination. In particular, microglia have been suggested to have both neuroprotective and neurotoxic effects on the brain. Investigation into seizure termination is of particular interest, as it is sometimes followed by a postictal generalized EEG suppression (PGES) - a low activity state that is potentially associated with sudden unexpected death in epilepsy. In this study, we attempt to link glial effects - synaptic pruning and astrocytic potassium clearance - to the duration of spontaneous epileptiform discharges (SEDs) as well as interSED intervals (iSEDs). We build upon an earlier model of a neuroglial network by translating it into the cortical paradigm and including microglial units. Preliminary findings of our model demonstrated that the duration of SEDs is largely determined by the astrocytic potassium clearance, whereas iSEDs significantly increased with microglial-driven synaptic pruning. In our model, astrocytic potassium clearance itself did not bring a PGES-like state, whereas microglial effects did, which suggests a potential biomarker for PGES phenomena.

Effects of astrocytic mechanisms on neuronal hyperexcitability

Epileptic seizures affect one in hundred people and about 30% of all patients don’t benefit from medication and have to rely on other intervention methods. Current computer models of epilepsy frequently focus on neurons and their interactions to explain both the normal and pathological events in the brain. Recent research has linked glial cell to various cellular processes that are necessary for signal generation and propagation [1]. Several mechanisms by which glial cells could influence the rest of the network have been proposed. One mechanism is the effect of potassium clearance on maintaining homeostatic ion concentration in the extracellular matrix which, when impaired, could lead to seizure-like activity [2]. In addition to directly affecting potassium concentration in the extracellular space (ECS), impaired astrocytes become unable to maintain acceptable intracellular chloride concentrations in the neurons, which can cause or extend seizure-like events [3]. We introduce a computational model of CA3 region of hippocampus, consisting of a network of an astrocyte and a pyramidal cell with a feedback inhibited interneuron, to investigate the effects of a) potassium clearance and buffering by glial cells, and b) calcium propagation on neuronal hyperexcitability. Each cell was represented using modified Traub’s compartment models [4]. Glial contribution was split into two separate factors – K+ clearance and buffering, partially revised from Oyehaug [5] and calcium interactions. We observe that when potassium clearing mechanisms are present (including inwardly rectifying potassium channel as well as phenomenologically represented spatial buffering), neuronal spiking occurs at normal rates (Figure ​(Figure1A).1A). However when these mechanisms are compromised, potassium accumulation occurs and seizure-like spike trains appear. Preliminary model findings point to both (a) the existence of depolarization block within model parameter searches and (b) the significant influence of glial calcium signaling on spontaneous neuronal discharges. Figure 1 Effects of astrocytic potassium clearance from extracellular space (ECS). (A) Somatic voltage recorded in an interneuron under working potassium clearance. (B) Somatic voltage when clearance mechanisms are disabled and potassium accumulates in the ECS. ...

Role of astrocytes in the clearance of excess extracellular potassium

The development of concepts describing potassium clearance mechanisms in the mammalian central nervous system in the last 35 years is reviewed. The pattern of excess potassium in the extracellular space is discussed as are the implications of these potassium levels for neuronal excitability. There is a systematic description of the available evidence for astrocytic involvement in situ. The three possible astrocytic potassium clearance mechanisms are introduced: spatial buffer mechanism; carrier-operated potassium chloride uptake as well as channel-operated potassium chloride uptake. The three mechanisms are compared and their compatibility is discussed. Evidence is now available showing that at least two of these if not all three mechanisms co-exist and complement each other. Finally, it is concluded that these potassium movements are not used as a signal system, only as a homeostatic feedback mechanisms. Such a genuine signal system involving glial elements exists — but it is based on calcium waves.