Selective Alterations in GABAAReceptor Subtypes in Human Temporal Lobe Epilepsy

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Abstract
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 (alpha1, alpha2, alpha3, beta2,3, and gamma2) 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 alpha-subunit variants observed in controls was markedly changed in surviving neurons. In granule cells, prominent upregulation mainly of the alpha2-subunit was seen on somata and apical dendrites with reduced labeling on basal dendrites. In CA2, differential rearrangement of all three alpha-subunits occurred. Moreover, there was layer-specific loss of alpha1-subunit-immunoreactive interneurons in hippocampus proper, whereas surviving interneurons exhibited extensive changes in dendritic morphology. Throughout, expression patterns of beta2,3- and gamma2-subunits largely followed those of alpha-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.