Symposia
Glial dysfunction and intractable epilepsy - from basic to clinical studies -／グリア細胞の機能異常と難治性てんかん ー基礎から臨床までー |
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| 3S2-1
Glia, DC shifts/red slow, and epilepsy
Akio Ikeda
Department of Epilepsy, Movement Disorders and Physiology, Kyoto University Graduate School of Medicine
Clinical EEG provides us with diagnostic information of epileptogenicity by epileptiform discharges, i.e., spikes, sharp waves, which reflect the paroxysmal depolarization shifts (PDS) in the epileptic neurons. Currently advanced technology has enabled us to record wide-band EEG: direct current (DC) shifts and high frequency oscillation (HFO). The both conditions could widen the neurophysiological definition of epiletgenicity. Ictal DC shifts was recorded by using a DC amplifier in 1960s with technical difficulty, but recently is by applying very small low frequency filter (0.016Hz) of an AC amplifier which has the large input impedance more than 200 mega-ohm without difficulty in patients with invasive electrodes (Ikeda et al., 1996,1997,1999, 2008). Once HFO is thought to highly reflect epileptogenicity in human epilepsy, we have investigated both ictal DC shifts and HFO simultaneously in patients with intractable partial epilepsy by means of subdural electrodes (Imamura et al., 2011: Kanazawa et al., 2015). Ictal DC shifts occurred earlier than or as early as ictal HFO significantly. It could suggest more active role of glia not only in the generating DC shifts but also presumably in ictogenesis. It is hypothesized as “the active DC shifts” as opposed to “the passive DC shifts” in acute symptomatic seizures. Namely, potassium hometostasis with Kir4.1 channel activity in the astrocytes as the functional syncytium may play an important role both after seizure and immediately before seizure generation. Glia may be an also a target of the drug to suppress the seizures and a potential index of epileptogenic area from both electrophysiological and neuroimaging points of view. | | 3S2-2
Alterations of glial cells in epileptogenic regions of the brain: a pathophysiological study
Akiyoshi Kakita，Hiroki Kitaura
Dept Pathology, Brain Res Inst, Niigata Univ
Seizure activities often originate from a localized region of the cerebral cortex and spread across large areas of the brain. The properties of these spreading abnormal discharges may account for the clinical phenotypes seen in epilepsy patients, although the underlying mechanisms and role of glial cells are not well understood. We investigated epileptiform activities ex vivo using epileptogenic brain tissue surgically resected from patients with partial epilepsy caused by various symptomatic lesions. Flavoprotein fluorescence imaging and local field potential recordings of hippocampal specimens taken from patients with mesial temporal lobe epilepsy (MTLE) revealed that the epileptiform activity, including high-frequency oscillations (HFOs), was often observed in the subiculum, and not in the hippocampus proper. As the extracellular K+ concentration ([K+]o) in the medium used for acute culture of the hippocampal tissue slices increased from 3mM to 12mM, the peak frequency of HFOs became significantly higher in specimens from MTLE patients with hippocampal sclerosis than in those from patients without hippocampal sclerosis, suggesting impairment of the extracellular K+ clearance mechanisms (known as spatial K+ buffering) in the subiculum. Loss of immunoreactivity for inwardly rectifying K+ channel 4.1 (Kir 4.1) was also evident in astrocytes in the subiculum. These findings suggest that impairment of homeostatic [K+]o by glial Kir4.1 may play a pivotal role in the development of MTLE. | | 3S2-3
Role of astrocytic Kir4.1 channels in modulating epileptogenesis
Yukihiro Ohno
Lab Pharmacol, Osaka Univ Pharm Sci
Neurotransmission is mediated by tripartite synapses which consist of not only neural, but also glial components, implying that astrocytes play important functions in regulating neuronal activity. Among these functions, “spatial potassium buffering” by astrocytes is critical in maintaining neuronal excitability, which removes excess extracellular K+ from synapses of high neuronal activity. The potassium buffering currents were conducted by the inwardly rectifying potassium (Kir) channels containing Kir4.1 subunits (Kir4.1 channels), which are specifically expressed in astrocytes. Recent advances revealed that reduced expression or dysfunction of Kir4.1 channels seems to be involved in generation of epileptic seizures both in animal models and patients with epilepsy. In addition, recent clinical studies have shown that loss-of-function mutations of the human Kir4.1 gene (KCNJ10) evoked EAST/SeSAME syndrome manifesting seizures. Although the precise mechanisms remain to be clarified, it is suggested that dysfunction of Kir4.1 channels disrupts spatial potassium buffering, elevates extracellular levels of K+ and glutamate, and causes abnormal neural excitation in the limbic regions and neocortex. In addition, we recently found the dysfunction of Kir4.1 channels facilitated the BDNF expression in cultured astrocytes. All these findings suggest that Kir4.1 channels control not only the seizure generation, but also the epileptogenesis, and can serve as a novel therapeutic target for epilepsy. | | 3S2-4
Epileptogenic astrocytes
Schuichi Koizumi
Dept Neuropharmacol, Interdisciplinary Grad Sch Med, Univ Yamanashi
Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy, partly characterized by hippocampus sclerosis. Recent accumulating evidence show that changes in glial cells are obvious in TEL, but an involvement of glial changes in TLE is still a matter of debate and a causal relationship between glial dysfunction and epileptogenesis is total unkown. Here, we show that status epilepticus (SE) induced activation of microglia, which was followed by induction of “epileptogenic astrocytes” in the hippocampus. Pilocarpine (Pilo) was used to induce SE in male adult B6 mice. Morphological and functional changes in glia were assessed by immunofluorescent analysis and Ca2+ imaging in the hippocampal slices, respectively. Pilo increased a quick and transient microglial activation (1-3 days after SE), which was followed by sustained activation of astrocytes in the hippocampus (7-28 days after SE). Twenty-eight days after SE, the mice showed susceptibility to Pilo, suggesting that epileptogenesis is induced at this time point.. At 28 days, reactive astrocytes displayed excess Ca2+ excitability, which was independent of neuronal activities and dependent on astrocytic IP3 receptors. Deletion of astrocytic IP3 receptors resulted in reduction of Ca2+ excitabilities, and importantly, inhibition of epileotogenesis. Taken together, after SE, astrocytes become “epileptogenic astrocytes”, whose aberrant Ca2+ excitability should be a cause of epileotogenesis. | |
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