Cell Volume Control in Healthy Brain and Neuropathologies

Abstract

Regulation of cellular volume is a critical homeostatic process that is intimately linked to ionic and osmotic balance in the brain tissue. Because the brain is encased in the rigid skull and has a very complex cellular architecture, even minute changes in the volume of extracellular and intracellular compartments have a very strong impact on tissue excitability and function. The failure of cell volume control is a major feature of several neuropathologies, such as hyponatremia, stroke, epilepsy, hyperammonemia, and others. There is strong evidence that such dysregulation, especially uncontrolled cell swelling, plays a major role in adverse pathological outcomes. To protect themselves, brain cells utilize a variety of mechanisms to maintain their optimal volume, primarily by releasing or taking in ions and small organic molecules through diverse volume-sensitive ion channels and transporters. In principle, the mechanisms of cell volume regulation are not unique to the brain and share many commonalities with other tissues. However, because ions and some organic osmolytes (e.g., major amino acid neurotransmitters) have a strong impact on neuronal excitability, cell volume regulation in the brain is a surprisingly treacherous process, which may cause more harm than good. This topical review covers the established and emerging information in this rapidly developing area of physiology.

Late adolescence mortality in mice with brain-specific deletion of the volume-regulated anion channel subunit LRRC8A

“…However, the volume of brain interstitial space does not stay constant and is dynamically reduced during neuronal excitation, mostly due to the swelling of astrocytes which accumulate ions and neurotransmitters (e.g., (Svoboda and Sykova 1991;Andrew and MacVicar 1994;Holthoff and Witte 1996;Haj-Yasein et al 2012), and reviews (Sykova and Nicholson 2008;Wilson and Mongin 2018)). Deletion of LRRC8A-containing VRAC results in the loss of cell volume regulation, including in brain cells (Qiu et al 2014;Voss et al 2014;Formaggio et al 2019), and may blunt homeostatic control of extracellular space.…”

“…Deletion of LRRC8A-containing VRAC results in the loss of cell volume regulation, including in brain cells (Qiu et al 2014;Voss et al 2014;Formaggio et al 2019), and may blunt homeostatic control of extracellular space. The persistent cellular swelling during periods of enhanced neuronal activity is sufficient to produce hyperexcitation due to changes in the extracellular K + and excitatory neurotransmitter levels (Wilson and Mongin 2018;Murphy et al 2017). In fact, such swelling has been proposed as an important driving cause in epileptogenesis (Traynelis and Dingledine 1989;Andrew 1991;Binder et al 2004;Murphy et al 2017;Wilson and Mongin 2018).…”

“…The persistent cellular swelling during periods of enhanced neuronal activity is sufficient to produce hyperexcitation due to changes in the extracellular K + and excitatory neurotransmitter levels (Wilson and Mongin 2018;Murphy et al 2017). In fact, such swelling has been proposed as an important driving cause in epileptogenesis (Traynelis and Dingledine 1989;Andrew 1991;Binder et al 2004;Murphy et al 2017;Wilson and Mongin 2018). This mechanism would be strongly underestimated in brain slice preparations because they have no limitations for activity-dependent tissue expansion.…”

“…This approach revealed tissue-specific contributions of VRAC to reproductive function (spermatogenesis), regulation of adipocyte size, insulin signaling, glucose homeostasis, and innate immunity (Luck et al 2018;Bao et al 2018;Zhang et al 2017;Kang et al 2018;Zhou et al 2020). Although the central nervous system (CNS) has long been considered to be the tissue with the highest sensitivity to cell volume alterations and VRAC activity (Kimelberg and Mongin 1998;Kimelberg 2005;Mongin 2007;Mongin 2016;Wilson and Mongin 2018), few studies have analyzed the functional significance of LRRC8 proteins in the brain. Our group was the first to uncover a key role for LRRC8Acontaining channels in swelling-and agonist-activated release of excitatory neurotransmitters from astrocytes and explore the molecular composition of the endogenous LRRC8 heteromers in brain cells Schober et al 2017).…”

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

“…The resulting membrane depolarization then creates an inwardly directed driving force for Cl − via anion channels, which in turn causes the additional influx of Na + and K + in order to achieve charge neutralization. This mechanism of cell swelling has been coined in the literature as Donnan cell swelling (Kimelberg, 2005;Wilson and Mongin, 2018). Moreover, the ATP sensitive SUR1-transient receptor potential melastatin 4 channels, which can operate without energy supply, play a significant role in the astrocytic swelling located in the ATP-depleted areas (Chen and Simard, 2001;Chen et al, 2003).…”