Neurological disorders: Inhibition: too much of a good thing?

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A new paper reveals that enhanced neuronal inhibition causes seizures in several animal models of absence epilepsy.

Absence seizures, characterized by a spike and wave discharge (SWD) pattern in thalamocortical networks, occur in many types of epilepsy. The cellular mechanisms underlying these seizures are unclear; however, a new paper by Cope et al. reveals that enhanced neuronal inhibition causes seizures in several animal models of absence epilepsy.


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It has been suggested that reduced GABA ( gamma -aminobutyric acid) type A receptor (GABA_AR)-mediated inhibition might cause absence seizures; however, there is confounding evidence for this hypothesis and the precise contribution of neuronal inhibition to seizures has remained elusive. As most GABA_AR-mediated inhibition of thalamocortical neurons is 'tonic' — persistent inhibition resulting from the action of ambient GABA on delta -subunit-containing extrasynaptic receptors — Cope et al. examined the contribution of tonic inhibition to absence seizures.

The authors found that treating rat brain slices with two drugs — GHB and THIP — that cause seizures in animal models significantly increased the amplitude of tonic GABA_AR currents in thalamocortical neurons. Similarly, tonic inhibitory currents were increased in slices taken from several genetic models of absence epilepsy, including GAERS (genetic absence epilepsy rats from Strasbourg) rats and two mutant mouse strains that exhibit absence seizures — stargazer and lethargic. Thus, increased tonic GABAergic inhibition is a common feature of several absence seizure models.

To determine how important this enhanced tonic inhibition is for seizures, the authors examined mice in which extrasynaptic GABA_AR activity was impaired by deletion of the GABA_AR delta -subunit. GHB did not cause seizures in these mice, suggesting that GABA_AR activity is required for seizures. Seizures were also reduced in GAERS rats in which the GABA_AR delta -subunit was knocked down using antisense oligodeoxynucleotides. Furthermore, specific treatment of thalamocortical neurons with THIP, which selectively increases tonic GABA_AR currents, was sufficient to cause seizures in otherwise normal rats.

What causes the enhanced inhibition in animal models of absence seizures? The authors asked whether reduced GABA reuptake by the astrocytic GABA transporters GAT-1 and GAT-3 (also known as GAT-2) might be at fault. Blocking either GAT-1 or GAT-3 boosted tonic currents in control animals; however, in GAERS rats and stargazer mice, in which these currents are already high, only blocking GAT-3 further enhanced them. This implies that reduced reuptake of GABA by GAT-1, resulting in high levels of ambient GABA, underlies the increased tonic currents observed in these animals. Indeed, mice and rats in which GAT-1 was deleted or blocked pharmacologically exhibited seizures.

These findings suggest that enhanced, rather than reduced, tonic inhibition is a common cause of seizures in several animal models of absence epilepsy and may provide new targets for therapeutic intervention. How the enhanced inhibition contributes to seizure generation is a question for future studies.

Katherine Whalley

References

Cope, D. W. et al. Enhanced tonic GABA_A inhibition in typical absence epilepsy. Nature Med. 15, 1392–1398 (2009) | Article | PubMed |