Αlpha 5 Subunit-Containing GABAA Receptors in Temporal Lobe Epilepsy with Normal MRI

GABA(A) receptors containing the alpha 5 subunit mediate tonic inhibition and are widely expressed in the limbic system. In animals, activation of alpha 5-containing receptors impairs hippocampus-dependent memory. Temporal lobe epilepsy is associated with memory impairments related to neuron loss and other changes. The less selective PET ligand [C-11]flumazenil has revealed reductions in GABA(A) receptors. The hypothesis that alpha 5 subunit receptor alterations are present in temporal lobe epilepsy and could contribute to impaired memory is untested. We compared alpha 5 subunit availability between individuals with temporal lobe epilepsy and normal structural MRI ('MRI-negative') and healthy controls, and interrogated the relationship between alpha 5 subunit availability and episodic memory performance, in a cross-sectional study. Twenty-three healthy male controls (median +/- interquartile age 49 +/- 13 years) and 11 individuals with MRI-negative temporal lobe epilepsy (seven males; 40 +/- 8) had a 90-min PET scan after bolus injection of [C-11]Ro15-4513, with arterial blood sampling and metabolite correction. All those with epilepsy and six controls completed the Adult Memory and Information Processing Battery on the scanning day. 'Bandpass' exponential spectral analyses were used to calculate volumes of distribution separately for the fast component [V-F; dominated by signal from alpha 1 (alpha 2, alpha 3)-containing receptors] and the slow component (V-S; dominated by signal from alpha 5-containing receptors). We made voxel-by-voxel comparisons between: the epilepsy and control groups; each individual case versus the controls. We obtained parametric maps of V-F and V-S measures from a single bolus injection of [C-11]Ro15-4513. The epilepsy group had higher V-S in anterior medial and lateral aspects of the temporal lobes, the anterior cingulate gyri, the presumed area tempestas (piriform cortex) and the insulae, in addition to increases of similar to 24% and similar to 26% in the ipsilateral and contralateral hippocampal areas (P<0.004). This was associated with reduced V-F:V-S ratios within the same areas (P<0.009). Comparisons of V-S for each individual with epilepsy versus controls did not consistently lateralize the epileptogenic lobe. Memory scores were significantly lower in the epilepsy group than in controls (mean 6 standard deviation similar to 0.4 +/- 1.0 versus 0.7 +/- 0.3; P = 0.02). In individuals with epilepsy, hippocampal V-S did not correlate with memory performance on the Adult Memory and Information Processing Battery. They had reduced V-F in the hippocampal area, which was significant ipsilaterally (P = 0.03), as expected from [C-11]flumazenil studies. We found increased tonic inhibitory neurotransmission in our cohort of MRI-negative temporal lobe epilepsy who also had co-morbid memory impairments. Our findings are consistent with a subunit shift from alpha 1/2/3 to alpha 5 in MRI-negative temporal lobe epilepsy.