Αlpha 5 subunit-containing GABAA receptors in temporal lobe epilepsy with normal MRI

Abstract

GABAA receptors containing the α5 subunit mediate tonic inhibition and are widely expressed in the limbic system. In animals, activation of α5-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 [11C]flumazenil has revealed reductions in GABAA receptors. The hypothesis that α5 subunit receptor alterations are present in temporal lobe epilepsy and could contribute to impaired memory is untested. We compared α5 subunit availability between individuals with temporal lobe epilepsy and normal structural MRI (‘MRI-negative’) and healthy controls, and interrogated the relationship between α5 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 [11C]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 [VF; dominated by signal from α1 (α2, α3)-containing receptors] and the slow component (VS; dominated by signal from α5-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 VF and VS measures from a single bolus injection of [11C]Ro15-4513. The epilepsy group had higher VS 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 ∼24% and ∼26% in the ipsilateral and contralateral hippocampal areas (P < 0.004). This was associated with reduced VF:VS ratios within the same areas (P < 0.009). Comparisons of VS 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 ± standard deviation −0.4 ± 1.0 versus 0.7 ± 0.3; P = 0.02). In individuals with epilepsy, hippocampal VS did not correlate with memory performance on the Adult Memory and Information Processing Battery. They had reduced VF in the hippocampal area, which was significant ipsilaterally (P = 0.03), as expected from [11C]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 α1/2/3 to α5 in MRI-negative temporal lobe epilepsy.

Increased expression of GABAA receptor subunits associated with tonic inhibition in patients with temporal lobe epilepsy

“…It is worth to emphasize that the PET study by McGinnity et al 44 and our histochemical data demonstrate an abundant expression of α5-containing GABA A receptors in the human hippocampus including the dentate gyrus. In rodents, α5-containing GABA A receptors, although abundant on dendrites of pyramidal neurons of hippocampal sector CA3, the subiculum and the entorhinal cortex, are expressed only at low concentrations in the molecular layer of the dentate gyrus.…”

“… 18 , 36 , 37 In rodents stimulation of α5-containing receptors in sector CA1 impairs the performance in hippocampus-dependent learning and memory tests 56 , 57 and the reverse α5-specific GABA A agonist PWZ-029 improves the performance of rats in the object recognition test. 58 In their PET study, McGinnity et al 44 showed a negative correlation between α5-selective binding and the performance in a cognitive test battery also in human controls and MRI negative TLE patients. 44 Interestingly, the α5-selective PET signal V S was, however, negatively correlated with interictal intervals reflecting an association of increased [ 11 C]Ro15-4513 uptake with decreased seizure activity and points to a possible anticonvulsive action mediated by α5-containing receptors.…”

“… 58 In their PET study, McGinnity et al 44 showed a negative correlation between α5-selective binding and the performance in a cognitive test battery also in human controls and MRI negative TLE patients. 44 Interestingly, the α5-selective PET signal V S was, however, negatively correlated with interictal intervals reflecting an association of increased [ 11 C]Ro15-4513 uptake with decreased seizure activity and points to a possible anticonvulsive action mediated by α5-containing receptors. Respective receptors located on granule cell dendrites could importantly contribute to such a mechanism.…”

“…The histochemical data on the increased expression of the α5-subunit in TLE patients is in striking accordance with a recent elegant PET study by. 44 The authors investigated the uptake of [ 11 C]Ro15-4513, a partial inverse benzodiazepine agonist for α5 subunit-containing GABA A receptors in MRI-negative (non-lesional) TLE patients and non-epilepsy controls. [ 11 C]Ro15-4513 binds to α1-, α2-, α3- and to α5-containing receptors.…”

“… 46 , 47 Taken together, these data indicate a loss in subunits α1, α2 or α3 in the seizure focus, whereas receptors containing α5 are upregulated. McGinnity et al 44 therefore interpreted their data as a shift from α1-, α2- or α3- to α5-containing receptors.…”