Abstract
Astrocytes, the major type of non-neuronal cells in the brain, play an important functional role in extracellular potassium ([K+]o) and pH homeostasis. Pathological brain states that result in [K+]o and pH dysregulation have been shown to cause astrocyte swelling. However, whether astrocyte volume changes occur under physiological conditions is not known. In this study we used two-photon imaging to visualize real-time astrocyte volume changes in the stratum radiatum of the hippocampus CA1 region. Astrocytes were observed to swell by 19.0±0.9% in response to a small physiological increase in the concentration of [K+]o (3 mM). Astrocyte swelling was mediated by the influx of bicarbonate (HCO3−) ions as swelling was significantly decreased when the influx of HCO3− was reduced. We found: 1) in HCO3− free extracellular solution astrocytes swelled by 5.4±0.7%, 2) when the activity of the sodium-bicarbonate cotransporter (NBC) was blocked the astrocytes swelled by 8.3±0.7%, and 3) in the presence of an extracellular carbonic anhydrase (CA) inhibitor astrocytes swelled by 11.4±0.6%. Because a significant HCO3− efflux is known to occur through the γ-amino-butyric acid (GABA) channel, we performed a series of experiments to determine if astrocytes were capable of HCO3− mediated volume shrinkage with GABA channel activation. Astrocytes were found to shrink −7.7±0.5% of control in response to the GABAA channel agonist muscimol. Astrocyte shrinkage from GABAA channel activation was significantly decreased to −5.0±0.6% of control in the presence of the membrane-permeant CA inhibitor acetazolamide (ACTZ). These dynamic astrocyte volume changes may represent a previously unappreciated yet fundamental mechanism by which astrocytes regulate physiological brain functioning.
Highlights
Neuronal firing of action potentials leads to the release of potassium ions (K+) into the extracellular space (ECS) of neural tissue and CO2 extrusion from the active neurons causes localized pH changes in the ECS
The currently available literature reflects only what might be occurring during pathological states [16], and whether volume changes may be an intrinsic phenomenon of astrocytes that occurs during physiological brain functioning is not known
To determine whether astrocyte swelling might occur under non-pathological conditions, hippocampal slices were perfused with artificial cerebrospinal fluid (ACSF) containing 5.5 mM [K+]o from an initial control ACSF containing 2.5 mM [K+]o
Summary
Neuronal firing of action potentials leads to the release of potassium ions (K+) into the extracellular space (ECS) of neural tissue and CO2 extrusion from the active neurons causes localized pH changes in the ECS. Astrocytes undergo dramatic volume changes as a result of the ionic dysregulation that occurs during pathological brain states such as ischemia, trauma and epilepsy [6,7,8,9]. Astrocytes rapidly undergo an intracellular alkalinization in response to modest increases in [K+]o [2,19]. This alkalinization is dependent on the uptake of the bicarbonate ion (HCO32), and can be blocked with the removal of extracellular HCO32, or by inhibition of the main astrocyte HCO32 transporter, the sodiumbicarbonate cotransporter (NBC) [20,21]. Reversible changes in the size and diffusion properties of the ECS have been shown to occur under physiological conditions, which have been documented in response to neuronal activity [6,8,22,23]
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