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 language | English |
|---|---|
| Pages (from-to) | 15219-15223 |
| Number of pages | 5 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 102 |
| Issue number | 42 |
| DOIs | |
| Publication status | Published - Oct 18 2005 |
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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 journal › Article
}
TY - JOUR
T1 - Rundown of GABA type A receptors is a dysfunction associated with human drug-resistant mesial temporal lobe epilepsy
AU - Ragozzino, D.
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.
PY - 2005/10/18
Y1 - 2005/10/18
N2 - 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.
AB - 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.
KW - Human slices
KW - Xenopus oocytes
UR - http://www.scopus.com/inward/record.url?scp=27244436279&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=27244436279&partnerID=8YFLogxK
U2 - 10.1073/pnas.0507339102
DO - 10.1073/pnas.0507339102
M3 - Article
C2 - 16217016
AN - SCOPUS:27244436279
VL - 102
SP - 15219
EP - 15223
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 42
ER -