GABAergic transmission in temporal lobe epilepsy: the role of neurosteroids

Abstract

Modification of GABAergic inhibition is an intensely investigated hypothesis guiding research into mechanisms underlying temporal lobe epilepsy (TLE). Seizures can be initiated by blocking γ amino butyric acid type A (GABAA receptors, GABARs), which mediate fast synaptic inhibition in the brain, and controlled by drugs that enhance their function. Derivatives of steroid hormones called neurosteroids are natural substances that physiologically enhance GABAR function and suppress seizures. GABAR structure, function, expression, assembly, and pharmacological properties are changed in the hippocampus of epileptic animals. These alterations render GABARs less sensitive to neurosteroid modulation, which may contribute to seizure susceptibility. Plasticity of GABARs could play a role in periodic exacerbation of seizures experienced by women with epilepsy, commonly referred to as catamenial epilepsy.

Figure 1

Finasteride increased frequency of spontaneous seizures in epileptic animals. A: Administration of 100 mg/kg finasteride, a 5α reductase enzyme blocker, increased the frequency of spontaneous seizures in female epileptic animals (n=11). Increased seizure frequency returned to baseline 16–18 hrs after finasteride administration (inset) (modified from Lawrence et al, 2010). B: Treatment with finasteride (100 mg/kg) also increased frequency of spontaneous seizures in male epileptic animals (n=4). The seizures returned to baseline frequency 4–5 hrs after finasteride treatment (inset).

Figure 2

A schematic showing increased synaptic expression of α₄β_xγ₂ subunit-containing receptors, and reduced expression of α₄β_xδ subunit-containing receptors in the DGCs of epileptic animals. Expression of receptors with lower neurosteroid sensitivity is proposed to lower seizure threshold in epileptic animals, such that finasteride administration leads to seizure exacerbation.