Astrocytic Ca2+ Signaling in Epilepsy

Abstract

Epilepsy is one of the most common neurological disorders – estimated to affect at least 65 million worldwide. Most of the epilepsy research has so far focused on how to dampen neuronal discharges and to explain how changes in intrinsic neuronal activity or network function cause seizures. As a result, pharmacological therapy has largely been limited to symptomatic treatment targeted at neurons. Given the expanding spectrum of functions ascribed to the non-neuronal constituents of the brain, in both physiological brain function and in brain disorders, it is natural to closely consider the roles of astrocytes in epilepsy. It is now widely accepted that astrocytes are key controllers of the composition of the extracellular fluids, and may directly interact with neurons by releasing gliotransmitters. A central tenet is that astrocytic intracellular Ca2+ signals promote release of such signaling substances, either through synaptic or non-synaptic mechanisms. Accruing evidence suggests that astrocytic Ca2+ signals play important roles in both seizures and epilepsy, and this review aims to highlight the current knowledge of the roles of this central astrocytic signaling mechanism in ictogenesis and epileptogenesis.

Elevated photic response is followed by a rapid decay and depressed state in ictogenic networks

“…We hypothesized that such long‐lasting depressed state might be due to recruitment of astroglial networks that are shown to be important for clearing excess glutamate. 15 , 25 , 37 To test this hypothesis, we measured the astroglial calcium signals during photic stimulation. Astroglial calcium signals displayed strikingly different photic responses (Figure 6B ) when compared to the neurons (Figure 6A ).…”

“…We also observed that this hyperexcitable elevated state is often followed by a slow and long‐lasting depressed state, which is particularly prominent in the PTZ model. We hypothesized that such long‐lasting depressed state might be due to recruitment of astroglial networks that are shown to be important for clearing excess glutamate 15,25,37 . To test this hypothesis, we measured the astroglial calcium signals during photic stimulation.…”

Detection of astrocytic slow oscillatory activity and response to seizurogenic compounds using planar microelectrode array

“…Regarding the effect of calcium modulation, the results of inhibition experiments with cilnidipine showed dose-dependent decrease in astrocyte oscillations, and it was consistent with those reported by Fleischer et al ( Figure 3C ). In addition, many previous studies reported that intracellular Ca 2+ concentration in astrocytes dynamically changed in response to drugs ( Heuser and Enger, 2021 ). Therefore, changes in calcium concentration have a role in astrocyte oscillations observed in this study.…”

Abnormal Ca2+ Signals in Reactive Astrocytes as a Common Cause of Brain Diseases

“…Epilepsy not only results from overexcitation of neurons but also is a condition in which excitation occurs repeatedly. Thus, in addition to the clarification of ictogenesis and neuronal overexcitation, the mechanism by which epileptic seizures are repeated needs to be elucidated, or in other words, the mechanism that makes epilepsy more likely to occur needs to be determined [ 19 , 20 ]. This situation, in which the brain becomes prone to recurrent epileptic seizures is called epileptogenesis.…”

“…In this review, we will focus on aberrant Ca 2+ signals as a phenotype of reactive astrocytes. We show some examples of brain dysfunctions such as neuropathic pains [ 11 , 12 , 17 , 18 ], epileptogenesis [ 19 , 20 , 21 ], and Alexander disease (AxD) [ 22 ], where aberrant Ca 2+ signals in astrocytes are commonly observed and are highly involved in the cause of these pathogenesis.…”