Changes in Flip/Flop Splicing of Astroglial AMPA Receptors in Human Temporal Lobe Epilepsy

Seifert, Gerald; Schröder, Wolfgang; Hinterkeuser, Stefan; Schumacher, Thekla B.; Schramm, Johannes; Steinhäuser, Christian

doi:10.1046/j.1528-1157.43.s.5.10.x

Cited by 41 publications

(36 citation statements)

References 26 publications

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“…3C). Thus, these findings show that the mRNA from human TLE tissue induced the oocytes to acquire functional AMPA receptors whose desensitization is potently modulated by CTZ, a drug known to decrease the rate of AMPA receptor desensitization (18,21).…”

Section: Functional Expression Of Human Neurotransmittermentioning

confidence: 68%

Expression of human epileptic temporal lobe neurotransmitter receptors inXenopusoocytes: An innovative approach to study epilepsy

Palma

Esposito

Mileo

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Poly(A ؉ ) RNA was extracted from the temporal lobe (TL) of medically intractable epileptic patients which underwent surgical TL resection. Injection of this mRNA into Xenopus oocytes led to the expression of ionotropic receptors for ␥-aminobutyric acid (GABA), kainate (KAI) and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Membrane currents elicited by GABA inverted polarity at ؊15 mV, close to the oocyte's chloride equilibrium potential, were inhibited by bicuculline, and were potentiated by pentobarbital and flunitrazepam. These basic characteristics were also displayed by GABA currents elicited in oocytes injected with mRNAs isolated from human TL glioma (TLG) or from mouse TL. However, the GABA receptors expressed by the epileptic TL mRNA exhibited some unusual properties, consisting in a rapid current run-down after repetitive GABA applications and a large EC 50 (125 M). AMPA alone evoked very small or nil currents, whereas KAI induced larger currents. Nevertheless, upon cyclothiazide treatment, AMPA elicited substantial currents that, like the KAI currents, were inhibited by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Furthermore, the glutamate receptor 5 (GluR5) agonist, ATPA, failed to evoke an obvious current although both RT-PCR and Western blot analyses showed GluR5 expression in the epileptic TL. Oocytes injected with mouse TL or human TLG mRNAs generated KAI and AMPA currents similar to those evoked in oocytes injected with epileptic TL mRNA but, in contrast to these, the mouse TL and human TLG oocytes were also responsive to ATPA. Our findings are in accord with the concept that both a depression of GABA inhibition and a dysfunction of the KAI-receptor system maintain a high neuronal excitability that results in epileptic seizures.

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Section: Functional Expression Of Human Neurotransmittermentioning

confidence: 68%

Expression of human epileptic temporal lobe neurotransmitter receptors inXenopusoocytes: An innovative approach to study epilepsy

Palma

Esposito

Mileo

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…Impressively, several studies support the hypothesis that reduced or dysfunctional glial glutamate transporters in the hippocampus may trigger spontaneous seizures in patients with mesial temporal sclerosis [91] , yet the underlying mechanisms are unclear. However, functional and single-cell transcript analyses support the idea that enhanced expression of glutamic acid receptor 1 is responsible for the prolonged receptor responses observed in the hippocampal astrocytes of epilepsy patients with mesial temporal sclerosis [92,93] . This alteration predicts enhanced depolarization upon activation by endogenous glutamate.…”

Section: Gsk-3β And/or Elevate β-Catenin In Ng2 Cells or Gpcsmentioning

confidence: 94%

Roles of NG2 glial cells in diseases of the central nervous system

Zhao

2011

Neurosci. Bull.

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“…An elevated flip-to-flop mRNA ratio of the GluR1 splice variant is reported in reactive astrocytes from sclerotic hippocampi, suggesting an increase in responsiveness of these astrocytes to glutamate. 13,14 Immunoelectron microscopic examination of sclerotic hippocampi has revealed the expression of mGluR2/3, mGluR4, and mGluR8 in reactive astrocytes. In the same manner, mGluR3, mGluR5, and mGluR8 are reported to be up-regulated in the hippocampus in experimental animal models of TLE.…”

Section: Astrocyte Receptorsmentioning

confidence: 99%

Astrocytes and Epilepsy

2010

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Summary: Astrocytes form a significant constituent of seizure foci in the human brain. For a long time it was believed that astrocytes play a significant role in the causation of seizures. With the increase in our understanding of the unique biology of these cells, their precise role in seizure foci is receiving renewed attention. This article reviews the information now available on the role of astrocytes in the hippocampal seizure focus in patients with temporal lobe epilepsy with hippocampal sclerosis. Our intent is to try to integrate the available data. Astrocytes at seizure foci seem to not be a homogeneous population of cells, and in addition to typical glial fibrillary acidic protein, positive reactive astrocytes also include a population of neuron glia-2-like cells The astrocytes in sclerotic hippocampi differ from those in nonsclerotic hippocampi in their membrane physiology, having elevated Naϩ channels and reduced inwardly rectifying potassium ion channels, and some having the capacity to generate action potentials. They also have reduced glutamine synthetase and increased glutamate dehydrogenase activity. The molecular interface between the astrocyte and microvasculature is also changed. The astrocytes are also associated with increased expression of many molecules normally concerned with immune and inflammatory functions. A speculative mechanism postulates that neuron glia-2-like cells may be involved in creating a high glutamate environment, whereas the function of more typical reactive astrocytes contribute to maintain high extracellular Kϩ levels; both factors contributing to the hyperexcitability of subicular neurons to generate epileptiform activity. The functions of the astrocyte vascular interface may be more critical to the processes involved in epileptogenesis.

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Changes in Flip/Flop Splicing of Astroglial AMPA Receptors in Human Temporal Lobe Epilepsy

Cited by 41 publications

References 26 publications

Expression of human epileptic temporal lobe neurotransmitter receptors inXenopusoocytes: An innovative approach to study epilepsy

Expression of human epileptic temporal lobe neurotransmitter receptors inXenopusoocytes: An innovative approach to study epilepsy

Roles of NG2 glial cells in diseases of the central nervous system

Astrocytes and Epilepsy

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