Ca2+ Signals in Astrocytes Facilitate Spread of Epileptiform Activity

Abstract

Epileptic seizures are associated with increased astrocytic Ca2+ signaling, but the fine spatiotemporal kinetics of the ictal astrocyte–neuron interplay remains elusive. By using 2-photon imaging of awake head-fixed mice with chronic hippocampal windows we demonstrate that astrocytic Ca2+ signals precede neuronal Ca2+ elevations during the initial bout of kainate-induced seizures. On average, astrocytic Ca2+ elevations preceded neuronal activity in CA1 by about 8 s. In subsequent bouts of epileptic seizures, astrocytes and neurons were activated simultaneously. The initial astrocytic Ca2+ elevation was abolished in mice lacking the type 2 inositol-1,4,5-trisphosphate-receptor (Itpr2−/−). Furthermore, we found that Itpr2−/− mice exhibited 60% less epileptiform activity compared with wild-type mice when assessed by telemetric EEG monitoring. In both genotypes we also demonstrate that spreading depression waves may play a part in seizure termination. Our findings imply a role for astrocytic Ca2+ signals in ictogenesis.

Aberrant Calcium Signals in Reactive Astrocytes: A Key Process in Neurological Disorders

“…In adult mice, simultaneous Ca 2+ imaging from both neurons and astrocytes using two different colored GECIs revealed that astrocytes are activated earlier than neurons following seizure induced by intraperitoneal administration of kainate. Although the detailed mechanism underlying this astrocyte response is not clear, suppression of Ca 2+ responses by deletion of inositol-1,4,5 trisphosphate receptor type 2 (IP 3 R2, see below), in which astrocytes lack a major intracellular Ca 2+ release pathway, resulted in less kainate-induced epileptic activity recorded by electroencephalogram telemetry [38]. This indicates that astrocyte Ca 2+ signals are proconvulsive, which is consistent with previous reports [36].…”

Mapping optogenetically-driven single-vessel fMRI with concurrent neuronal calcium recordings in the rat hippocampus

“…Kunkler et al 72 have observed Ca 2+ waves occurring in neurons (~6 mm/min) and astrocytes (~4 mm/min) during SD initiation and propagation in hippocampal organ cultures. Meanwhile, in contrast to astrocytic Ca 2+ waves propagation speed of (2–3.3 mm/min) related to cortical SD in both rat and mouse neocortex 69,73,74 , Heuser et al 75 also reported a 6–8 mm/min propagation speed of SD Ca 2+ waves from both neurons and astrocytes in the hippocampal CA1 region. Interestingly, unique, spontaneous astrocytic Ca 2+ waves, which have been reported to propagate at ~4 mm/min in the hippocampus, do not show the long-term spreading depression features 76 .…”

Astrocyte Glutamate Uptake and Signaling as Novel Targets for Antiepileptogenic Therapy

“…Astrocytes play a critical role in the development and progression of epilepsy (7,8,30,(68)(69)(70)(71)(72)(73)(74)(75)(76). Astrocytic glutamate uptake is dysregulated in both preclinical models and in patients with TLE leading to increases in basal glutamate levels, and activation and signaling of astrocytic metabotropic glutamate receptors, mGluR3 and mGluR5, is also altered in animal models and patients with TLE.…”