Ion Homeostasis in Glia and Neurons

Ion Homeostasis in Neurons

The neuronal function depends critically on ion homeostasis. When neurons need the energy to maintain electrical and synaptic activity, they send out signals. These signals are received by neighboring glial cells and initiate a response. An obvious way to impact the neuronal firing properties is to modulate the ionic concentration in the extracellular compartment. Ideally, neurons restore equilibrium after neuronal activity by pumping back displaced Na⁺ and K⁺ ions and reuptake and recycling neurotransmitters. Therefore, maintaining the correct ionic concentration gradients is important for the functions of brain cells.

Ion Homeostasis in Glia

Glial can affect neuronal excitability by regulating ion homeostasis. Thus, glial cells are involved in regulating ion homeostasis and amino acid neurotransmitter metabolism, and the nutrient and energy support of neurons. Glial cells form a large panglial syncytium to aid the uptake and dispersal of ions and make extensive contacts with brain fluid barriers to disposing of excess ions. In addition, astrocytes play a determinant role in setting the firing mode of adjacent neurons by regulating extracellular ionic concentrations. Genetic defects in glial proteins involved in ion homeostasis disrupt brain functioning, thereby leading to neurological diseases.

Fig.1. Ion homeostasis in the panglial syncytium. (Min, 2018)

• Astrocytes and potassium homeostasis

Glial regulation of extracellular K⁺ can influence diverse aspects of neural circuit function, such as maintaining extracellular potassium K⁺ at a level compatible with continuous neuronal function. Astrocytes are connected by an extensive network of gap junctions that are permeable to K⁺. Activation of the potassium channels causes potassium ions to flow toward the extracellular space during neuronal discharge. As a result, the extracellular potassium concentration K⁺ can increase up to a ceiling level of ~12 mM in physiological conditions. Furthermore, astrocytes are responsible for bringing K⁺ back to resting values after an activity-driven increase. Thus, astrocytes form a syncytium for rapid redistribution of K⁺ from areas with high neuronal activity. Other mechanisms for K⁺ uptake in astrocytes could contribute to extracellular K⁺ homeostasis. However, this regulation of K⁺ is made mainly by a passive mechanism because of the high permeability of the glial membrane to potassium.

• Astrocytes and sodium homeostasis

The extracellular sodium concentration Na⁺ can be decreased due to the influx of sodium. Astrocytes express voltage-gated Na⁺ channels, which allow for a small influx of Na⁺ ions to ensure the maintenance of Na⁺ at concentrations required for the proper functioning of the Na⁺-K⁺ pump. The glial Na⁺-K⁺ pump, which is involved in K⁺ homeostasis, can also greatly impact neuronal sodium homeostasis.

• Astrocytes and calcium homeostasis

Neuronal activity is related to the decrease of the extracellular concentration of Ca²⁺ in parallel to the rise in Ca²⁺ due to calcium influx into the cells through the ion channels. In many brain areas, astrocytes possess calcium channels and express calcium sensors, and can effectively sense the level of calcium in the extracellular compartment. Therefore, the dysregulation of astrocytic functions and brain pathologies are linked with extracellular calcium. For example, Parkinson's disease results from an inefficient regulation of calcium levels in the extracellular space. A precursor sign of Parkinson's disease could then be a transient decrease of calcium in the extracellular space.

• Astrocytes and chloride homeostasis

The movements of chloride ions in response to neuronal activation are more complex than the other ions. Several chloride channels have been described in astrocytes, including volume-sensitive chloride channels. The participation of chloride channels in astrocytic volume change might result from their association with actin proteins. Chloride ions may be transported into the astrocyte by a Na⁺-K⁺-2Cl^- cotransporter and extruded via the Cl^-/HCO^- anion exchange system coupled to pH regulation.

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Reference

1. Min, R.; van der Knaap, M. S. Genetic defects disrupting glial ion and water homeostasis in the brain. Brain Pathology. 2018, 28(3), 372-387.