Hand, Kieran Sean Patrick; (1998) GABAA/benzodiazepine receptor distribution and subunit mRNA expression in human temporal lobe epilepsy. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The GABAA/central benzodiazepine receptor (cBZR) complex is a major inhibitory receptor in the vertebrate CNS. A functional impairment of GABAergic inhibition has been proposed as one mechanism which may underlie increased seizure susceptibility in human temporal lobe epilepsy (TLE). The objective of this study was to characterise abnormalities of the GABAA/cBZR in TLE with a correlative autoradiography, in-situ hybridisation, immunohistochemistry and quantitative neuropathology study. Hippocampal tissue was obtained at surgery from patients with intractable TLE due to hippocampal sclerosis (HS) and autopsies of neurologically normal controls. Neuronal densities were obtained using a 3-D counting method in paraffin-embedded sections. Saturation autoradiographic studies were performed on cryostat sections using [3H]-flumazenil and expression of mRNA encoding the α1-α6, β3 and γ2 subunits of the GABAA receptor was assessed using in-situ hybridisation histochemistry. Distribution of the receptor protein was also determined using immunohistochemistry with antibodies to the GABAA α1 and β2/3 subunits. A significant decrease in central benzodiazepine binding sites was demonstrated in all subfields of the human hippocampus in HS. This loss of cBZR binding sites would appear to be due primarily to changes in neuronal density characteristic of this pathology. However, in the CA 1 subfield, a reduced BZ receptor concentration was evident on surviving neurones in the HS group (p<0.05). Expression of mRNA encoding GABAA receptor subunits α1, α2, α4, α5, and γ2, was upregulated in surviving neurones of the granule cell layer of the dentate gyrus in HS. In addition, epilepsy-associated increases in the expression of mRNA encoding the α1 subunit were observed in the hilus and CA2 and α2 mRNA in the hilus and CA1. In contrast, an apparent decrease in expression of β3 mRNA per neurone was detected in CA1 in HS (p<0.07) and of γ2 in the CA2 in HS (p<0.10). These findings imply a functional abnormality of the GABAA/CBZR complex that may have a role in the pathophysiology of epileptogenicity in HS.

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