Turning down the volume: Astrocyte volume change in the generation and termination of epileptic seizures

Abstract

Approximately 1% of the global population suffers from epilepsy, a class of disorders characterized by recurrent and unpredictable seizures. Of these cases roughly one-third are refractory to current antiepileptic drugs, which typically target neuronal excitability directly. The events leading to seizure generation and epileptogenesis remain largely unknown, hindering development of new treatments. Some recent experimental models of epilepsy have provided compelling evidence that glial cells, especially astrocytes, could be central to seizure development. One of the proposed mechanisms for astrocyte involvement in seizures is astrocyte swelling, which may promote pathological neuronal firing and synchrony through reduction of the extracellular space and elevated glutamate concentrations. In this review, we discuss the common conditions under which astrocytes swell, the resultant effects on neural excitability, and how seizure development may ultimately be influenced by these effects.

Purinergic signaling in cochlear supporting cells reduces hair cell excitability by increasing the extracellular space

“…K + accumulation and depolarization of IHCs followed, an effect absent when IHC K + channels were inhibited ( Figure 3 J,K). This phenomenon is consistent with the depolarizing shift in the resting membrane potential of IHCs observed in Tmem16A cKO mice ( Wang et al, 2015 ), which similarly blocks ISC crenation, and with studies in the brain where inducing cell swelling with hypoosmotic solutions or impairing K + buffering results in neuronal epileptiform activity ( Larson et al, 2018 ; Murphy et al, 2017 ; Thrane et al, 2013 ). Basal P2RY1 activation in supporting cells therefore hyperpolarizes nearby IHCs in the developing cochlea by expanding the extracellular space and lowering local K + concentrations.…”

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

“…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).…”

Cell Volume Control in Healthy Brain and Neuropathologies

“…The term epilepsy encompasses a constellation of diseases with somewhat different etiologies, all of which manifest as recurrent, unprovoked seizures which are usually initiated in the cortical areas or the hippocampus and then spread throughout the brain (McNamara, 1994; McNamara, Huang, & Leonard, 2006). While the main focus of epilepsy research is on changes in neuronal cells, emerging studies also implicate the complex interactions between neurons and various classes of glia, with the potentially strong involvement of changes in glial gene expression, glutamate metabolism, cellular morphology and cell volume (McNamara et al, 2006; David et al, 2009; Eid, Williamson, Lee, Petroff, & de Lanerolle, 2008; Murphy, Binder, & Fiacco, 2017). As mentioned in the prior section, a hypoosmotic challenge on its own can cause brain hyperexcitability and seizures, strongly suggesting that cell volume is a highly relevant factor.…”