Central benzodiazepine receptor autoradiography in hippocampal sclerosis

Abstract

1. The γ-aminobutyric acid (GABA)_A/central benzodiazepine receptor (cBZR) complex is a major inhibitory receptor in the vertebrate CNS. Binding of [¹¹C]-flumazenil to this complex in vivo is reduced in hippocampal sclerosis (HS). It has been uncertain whether reduced cBZR binding is entirely due to neuronal loss in HS.

2. The objective of this study was to characterize abnormalities of the cBZR in HS with a correlative autoradiographic and quantitative neuropathological study.

3. Saturation autoradiographic studies were performed with [^†H]-flumazenil to investigate relationships between neuronal density and receptor availability (B_max) and affinity (K_d) in HS. Hippocampal tissue was obtained at surgery from 8 patients with intractable temporal lobe epilepsy (TLE) due to HS and autopsies of 6 neurologically normal controls. Neuronal densities were obtained by means of a 3-D counting method.

4. B_max values for [^†H]-flumazenil binding in the subiculum, CA1, CA2, CA3, hilus and dentate gyrus were all found to be significantly reduced in HS compared with controls and significant increases in affinity were observed in the subiculum, hilus and dentate gyrus. In HS, cBZR density in the CA1 region was significantly reduced (P<0.05) to a greater extent than could be attributable to neurone loss. In other regions, B_max was reduced in parallel with neuronal density.

5. In HS, there is a loss of cBZR in CA1 over and above loss of neurones. This finding and increases in affinity for flumazenil in subiculum, hilus and dentate gyrus imply a functional abnormality of the GABA_A/cBZR complex that may have a role in the pathophysiology of epileptogenicity in HS.

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