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The Journal of Neuroscience, July 15, 2000, 20(14):5401-5419

Selective Alterations in GABA_A Receptor Subtypes in Human Temporal Lobe Epilepsy

Fabienne Loup¹, Heinz-Gregor Wieser², Yasuhiro Yonekawa³, Adriano Aguzzi⁴, and Jean-Marc Fritschy¹

¹ Institute of Pharmacology, University of Zurich, and Departments of ² Neurology, ³ Neurosurgery, and ⁴ Neuropathology, University Hospital Zurich, 8057 Zurich, Switzerland

Temporal lobe epilepsy (TLE) is associated with impaired inhibitory neurotransmission. Studies in animal models suggest that GABA_A receptor dysfunction contributes to epileptogenesis. To understand the mechanisms underlying TLE in humans, it is fundamental to determine whether and how GABA_A receptor subtypes are altered. Furthermore, identifying novel receptor targets is a prerequisite for developing selective antiepileptic drugs. We have therefore analyzed subunit composition and distribution of the three major GABA_A receptor subtypes immunohistochemically with subunit-specific antibodies (1, 2, 3, 2,3, and 2) in surgical specimens from TLE patients with hippocampal sclerosis (n = 16). Profound alterations in GABA_A receptor subtype expression were observed when compared with control hippocampi (n = 10). Although decreased GABA_A receptor subunit staining, reflecting cell loss, was observed in CA1, CA3, and hilus, the distinct neuron-specific expression pattern of the -subunit variants observed in controls was markedly changed in surviving neurons. In granule cells, prominent upregulation mainly of the 2-subunit was seen on somata and apical dendrites with reduced labeling on basal dendrites. In CA2, differential rearrangement of all three -subunits occurred. Moreover, there was layer-specific loss of 1-subunit-immunoreactive interneurons in hippocampus proper, whereas surviving interneurons exhibited extensive changes in dendritic morphology. Throughout, expression patterns of 2,3- and 2-subunits largely followed those of -subunit variants. These results demonstrate unique subtype-specific expression of GABA_A receptors in human hippocampus. The significant reorganization of distinct receptor subtypes in surviving hippocampal neurons of TLE patients with hippocampal sclerosis underlines the potential for synaptic plasticity in the human GABA system.

Key words: human epilepsy; GABA_A receptor; dentate gyrus; hilus; CA2; pyramidal cells; granule cells; interneurons

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20145401-19$05.00/0

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