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Epilepsy Curr. 2006 July; 6(4): 138–139.
PMCID: PMC1783430

Inhibitory GABA Current Rundown in Epileptic Brain: Use-Dependent and Pathology-Specific Mechanisms

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 PP, Miledi R, Eusebi F

Proc Natl Acad Sci U S A 2005;102(42):15219–15223 [PubMed]

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 GABAA-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.


It is frequently noted that the percentage of epileptic patients who either intermittently or permanently develop pharmacoresistance has not changed appreciably, in spite of the development of novel antiepileptic drugs and significant therapeutic advances for other neurological disorders. Furthermore, since under most circumstances, freshly isolated human brain tissue from drug-responsive patients with epilepsy is not available, electrophysiological investigations have been almost exclusively performed with pharmacoresistant patients.

A number of experimental and clinical findings have addressed the pharmacodynamic mechanisms of drug-resistant epilepsy (e.g., ref. 1), including the data by Ragozzino and colleagues reviewed here. One of the ideal targets for antiepileptic drug therapy is the yin/yang of the excitation/inhibition imbalance that characterizes the epilepsies. GABA receptors obviously are key participants in this imbalance, and several antiepileptic drugs (e.g., diazepam and barbiturates) preferentially, if not selectively, enhance GABA inhibition (2). The exact rationale for the excitation/inhibition imbalance is not fully understood; however, loss of GABAergic interneurons and impaired inhibitory function often have been considered hallmarks of the epileptic brain (3). The experimental evidence supporting these concepts, however, is not conclusive, since increased GABA levels may actually cause synchronization of neuronal networks. (4). Regardless, it is clear that selective enhancement of inhibitory drive is highly desirable to treat neuronal hyperexcitability. The study by Ragozzino et al. suggests that altered GABA currents may account for excitability changes in seizure foci.

The experimental approach used by Ragozzino et al. is primarily electrophysiological but constitutes a departure from the usual patch-clamp recording techniques. The authors use a combination of patch-clamp recordings paired to a variation of the mRNA expression technique to study the development of GABA currents in frog oocytes. The novel aspect is the use of intact, presumably neuronal, membrane patches that are incorporated into the native oocytes' membranes. This technique is an important departure from mRNA expression studies, because it allows the study of the final product of transcription, expression, and trafficking. After membrane injection, the mechanism underlying the expression of receptors and channels is very different from what occurs following the injection of mRNA, as the appearance of receptors does not require de novo protein synthesis. It is thought that the foreign receptor-bearing membranes fuse with the oocyte membrane and cause the appearance of functional receptors.

The membrane injection technique is not devoid of pitfalls, since (i) the exact cellular origin of the membrane patches is not known, (ii) it is impossible to exactly quantify the percentage of GABA channels undergoing run down, and (iii) it may be that frog oocytes have a different propensity for GABA receptor insertion in their plasma membrane than do human neurons. Nevertheless, this unique approach has already yielded important results, such as demonstrating that GABA receptor affinity also is compromised in epileptic brain.

Interestingly, the authors also show that lesional epileptic brain is less prone to exaggerated GABA current rundown, compared to temporal-lobe–affected brain with no obvious lesional component. However, neurons from both cryptogenetic and symptomatic epileptic brain had equally reduced affinity for GABA. It is not clear whether the distinction between cryptogenetic and symptomatic epileptic brain is well justified in the context of the present work, but the finding at least seems to rule out the notion that history of seizures or antiepileptic drugs are the underlying mechanism of increased GABA current rundown, since both brain tissues experienced seizures and exposure to AEDs. The data also demonstrated that the loss of GABAergic signaling is use-dependent, since several agonist applications were needed to cause rundown of chloride currents. In intact brain or acutely isolated brain slices, it could be argued that rundown of an ionic current is due to dissipated or altered ionic gradients. Such an effect is less likely to occur in frog oocyte preparations, but the possibility that less-than-perfect ionic homeostasis in epileptic brain may play a role cannot be ruled out (5,6). Incidentally, a corollary to this finding is the fact that a use-dependent decrease in GABA function also may be partially responsible for relative insensitivity to GABAergic agonists. In fact, a diminished potency of GABA-related drugs would be expected because a similar use-dependent decline of GABA currents is likely to occur.

What have we learned from Ragozzino et al. regarding mechanisms of epileptogenesis and antiepileptic drug resistance? Will these findings influence treatment of patients or how drugs are designed? A possible treatment approach is suggested by the authors in a set of experiments that show that the brain-derived neurotrophic factor (BDNF) actually may reverse, in a tyrosine kinase (TrkB)-dependent fashion, the deficient GABAergic signaling. This finding opens a new and potentially exciting avenue for drug design in which enhancing BDNF levels or signaling may prove beneficial as a treatment for epileptic seizures that are intrinsically drug resistant to traditional antiepileptic treatment. As for any new and exciting finding in the field, caution is in order, since many other studies have shown a positive association between BNDF/TrkB and epileptogenesis (7).

In conclusion, the work by Ragozzino and colleagues supports the hypothesis that GABAergic function at inhibitory synapses is subjected to an abnormal current rundown in epileptic brain. A specific rundown of chloride currents was observed in a subset of patients, while changes in affinity for GABA were found in samples from all epileptic patients, regardless of the lesional or nonlesional diagnosis. Whether these changes in inhibitory neurotransmission are, as suggested by the authors, a specific etiological feature of focal seizures remains to be elucidated, as does the relationship of the findings to drug resistance.


1. Loscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci. 2005;6:591–602. [PubMed]
2. Najm I, Ying Z, Janigro D. Mechanisms of epileptogenesis. Neurol Clin. 2001;19:237–250. [PubMed]
3. Magloczky Z, Freund TF. Impaired and repaired inhibitory circuits in the epileptic human hippocampus. Trends Neurosci. 2005;28:334–340. [PubMed]
4. Avoli M, D'Antuono M, Louvel J, Kohling R, Biagini G, Pumain D, D'Arcangelo G, Tancredi V. Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro. Prog Neurobiol. 2002;68:167–207. [PubMed]
5. Bihi RI, Jefferys JG, Vreugdenhil M. The role of extracellular potassium in the epileptogenic transformation of recurrent GABAergic inhibition. Epilepsia. 2005;46(suppl 5):64–71. [PubMed]
6. Walz W, Hertz L. Functional interactions between neurons and astrocytes. II. Potassium homeostasis at the cellular level. Prog Neurobiol. 1983;20:133–183. [PubMed]
7. Koyama R, Ikegaya Y. To BDNF or not to BDNF: that is the epileptic hippocampus. Neuroscientist. 2005;11:282–287. [PubMed]

Articles from Epilepsy Currents are provided here courtesy of American Epilepsy Society