Rundown of GABA type A receptors is a dysfunction associated with human drug-resistant mesial temporal lobe epilepsy.
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 (GABA(A)-receptors) that display a marked rundown during repetitive applications of GABA. In contrast, GABA(A)-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 GABA(A)-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 GABA(A)-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 GABA(A)-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.
Ragozzino
D
D
Istituto Pasteur-Fondazione Cenci Bolognetti and Dipartimento di Fisiologia Umana e Farmacologia, Centro di Eccellenza Biologia e Medicina Molecolare, Università di Roma La Sapienza, Piazzale A. Moro 5, I00185 Rome, Italy.
Palma
E
E
Di Angelantonio
S
S
Amici
M
M
Mascia
A
A
Arcella
A
A
Giangaspero
F
F
Cantore
G
G
Di Gennaro
G
G
Manfredi
M
M
Esposito
V
V
Quarato
P P
PP
Miledi
R
R
Eusebi
F
F
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D004351:Drug Resistance / Q000502:physiology*; D004594:Electrophysiology; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D005260:Female; D006801:Humans; D008297:Male; D008845:Microinjections; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009865:Oocytes / Q000502:physiology; D011963:Receptors, GABA-A / Q000378:metabolism*; D013702:Temporal Lobe / Q000166:cytology / Q000378:metabolism; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D019208:Brain-Derived Neurotrophic Factor; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid