Rundown of GABA type A receptors is a dysfunction associated with human drug-resistant mesial temporal lobe epilepsy

D. Ragozzino, E. Palma, S. Di Angelantonio, M. Amici, A. Mascia, A. Arcella, F. Giangaspero, G. Cantore, G. Di Gennaro, M. Manfredi, V. Esposito, P. P. Quarato, R. Miledi, F. Eusebi

Research output: Contribution to journalArticle

Abstract

Pharmacotherapeutic strategies have been difficult to develop for several forms of temporal lobe epilepsy, which are consequently treated by surgical resection. To examine this problem, we have studied the properties of transmitter receptors of tissues removed during surgical treatment. We find that when cell membranes, isolated from the temporal neocortex of patients afflicted with drug-resistant mesial temporal lobe epilepsy (TLE), are injected into frog oocytes they acquire GABA type A receptors (GABAA-receptors) that display a marked rundown during repetitive applications of GABA. In contrast, GABAA-receptor function is stable in oocytes injected with cell membranes isolated from the temporal lobe of TLE patients afflicted with neoplastic, dysgenetic, traumatic, or ischemic temporal lesions (lesional TLE, LTLE). Use-dependent GABAA-receptor rundown is also found in the pyramidal neurons of TLE neocortical slices and is antagonized by BDNF. Pyramidal neurons in cortical slices of a traumatic LTLE patient did not show GABAA-receptor rundown. However, the apparent affinity of GABA A-receptor in oocytes microtransplanted with membranes from all of the epileptic patients studied was smaller than the affinity of receptors transplanted from the nonepileptic brain. We conclude that the use-dependent rundown of neocortical GABAA-receptor represents a TLE-specific dysfunction, whereas the reduced affinity may be a general feature of brains of both TLE and LTLE patients, and we speculate that our findings may help to develop new treatments for TLE and LTLE.

Original languageEnglish
Pages (from-to)15219-15223
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number42
DOIs
Publication statusPublished - Oct 18 2005

Fingerprint

Temporal Lobe Epilepsy
GABA-A Receptors
Pharmaceutical Preparations
Oocytes
Pyramidal Cells
Cell Membrane
Neocortex
Brain-Derived Neurotrophic Factor
Brain
Temporal Lobe
Anura
gamma-Aminobutyric Acid
Membranes
Therapeutics

Keywords

  • Human slices
  • Xenopus oocytes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Rundown of GABA type A receptors is a dysfunction associated with human drug-resistant mesial temporal lobe epilepsy. / Ragozzino, D.; Palma, E.; Di Angelantonio, S.; Amici, M.; Mascia, A.; Arcella, A.; Giangaspero, F.; Cantore, G.; Di Gennaro, G.; Manfredi, M.; Esposito, V.; Quarato, P. P.; Miledi, R.; Eusebi, F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 42, 18.10.2005, p. 15219-15223.

Research output: Contribution to journalArticle

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AU - Palma, E.

AU - Di Angelantonio, S.

AU - Amici, M.

AU - Mascia, A.

AU - Arcella, A.

AU - Giangaspero, F.

AU - Cantore, G.

AU - Di Gennaro, G.

AU - Manfredi, M.

AU - Esposito, V.

AU - Quarato, P. P.

AU - Miledi, R.

AU - Eusebi, F.

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