Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductances

Abstract

Functional properties of astrocytes were investigated with the patch-clamp technique in acute hippocampal brain slices obtained from surgical specimens of patients suffering from pharmaco-resistant temporal lobe epilepsy (TLE). In patients with significant neuronal cell loss, i.e. Ammon's horn sclerosis, the glial current patterns resembled properties characteristic of immature astrocytes in the murine or rat hippocampus. Depolarizing voltage steps activated delayed rectifier and transient K+ currents as well as tetrodotoxin-sensitive Na+ currents in all astrocytes analysed in the sclerotic human tissue. Hyperpolarizing voltages elicited inward rectifier currents that inactivated at membrane potentials negative to -130 mV. Comparative recordings were performed in astrocytes from patients with lesion-associated TLE that lacked significant histopathological hippocampal alterations. These cells displayed stronger inward rectification. To obtain a quantitative measure, current densities were calculated and the ratio of inward to outward K+ conductances was determined. Both values were significantly smaller in astrocytes from the sclerotic group compared with lesion-associated TLE. During normal development of rodent brain, astroglial inward rectification gradually increases. It thus appears reasonable to suggest that astrocytes in human sclerotic tissue return to an immature current pattern. Reduced astroglial inward rectification in conjunction with seizure-induced shrinkage of the extracellular space may lead to impaired spatial K+ buffering. This will result in stronger and prolonged depolarization of glial cells and neurons in response to activity-dependent K+ release, and may thus contribute to seizure generation in this particular condition of human TLE.

Loss of Astrocytic Domain Organization in the Epileptic Brain

“…This may lead to an increase of glutamate in astrocytes resulting in its excessive release, triggering synchronized depolarization of groups of neurons, or paroxysmal depolarization shifts (Tian et al, 2005). Reactive astrocytes have also been shown to downregulate inward rectifying K ϩ channels (Kir), specifically Kir4.1, in posttraumatic and temporal lobe epilepsy, leading to impairment of clearance of extracellular K ϩ , linked to neuronal hyperexcitability (Bordey and Sontheimer, 1998;Heinemann et al, 2000;Hinterkeuser et al, 2000;Schroder et al, 2000). In addition, aquaporin-4, the major water channel, loses its polarized location in astrocytic endfeet and becomes distributed across the entire cell body, potentially contributing to abnormalities of both water homeostasis and K ϩ buffering (Eid et al, 2005).…”

Astrocytes and Epilepsy

“…However, although both types are found in the nonsclerotic hippocampi from TLE patients, they report an almost complete loss of GluT cells in the CA1 region of the sclerotic hippocampus. 35 Furthermore, it was the GluR cells in the sclerotic tissue but not in the nonsclerotic hippocampus that had increased levels of the Flip isoform of GluR1. 14 …”

“…33,34 A third study found no increase. 35 The expression of voltage-dependent calcium channel a 1 subunits was examined by immunohistochemistry in sclerotic hippocampi from patients with TLE and compared to their expression in autopsy controls. 36 A signif-…”

“…Functional properties of astrocytes in acute hippocampal brain slices from patients with and without hippocampal sclerosis who were studied with the patch-clamp technique provided more direct evidence of defective Kir channels. 34,35,38 Hyperpolarizing voltages elicited inward rectifier currents that inactivated at membrane potentials Ϫ130 mV in astrocytes from nonsclerotic hippocampi, which were larger than those in the sclerotic tissue. Also the ratio of inward to outward K ϩ conductances showed that they were significantly smaller in astrocytes from the sclerotic hippocampi compared to those from the nonsclerotic ones.…”

“…Also the ratio of inward to outward K ϩ conductances showed that they were significantly smaller in astrocytes from the sclerotic hippocampi compared to those from the nonsclerotic ones. 35 The Kir4.1 subunit is involved in this defect. 38 …”