Selective alterations in GABA(A) receptor subtypes in human temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is associated with impaired inhibitory neurotr ansmission. Studies in animal models suggest that GABA(A) receptor dysfunct ion contributes to epileptogenesis. To understand the mechanisms underlying TLE in humans, it is fundamental to determine whether and how GABA(A) rece ptor subtypes are altered. Furthermore, identifying novel receptor targets is a prerequisite for developing selective antiepileptic drugs. We have the refore analyzed subunit composition and distribution of the three major GAB A(A) receptor subtypes immunohistochemically with subunit-specific antibodi es (alpha 1, alpha 2, alpha 3, beta 2,3, and gamma 2) in surgical specimens from TLE patients with hippocampal sclerosis (n = 16). Profound alteration s in GABA(A) receptor subtype expression were observed when compared with c ontrol hippocampi (n = 10). Although decreased GABA(A) receptor subunit sta ining, reflecting cell loss, was observed in CA1, CA3, and hilus, the disti nct neuron-specific expression pattern of the alpha-subunit variants observ ed in controls was markedly changed in surviving neurons. In granule cells, prominent upregulation mainly of the alpha 2-subunit was seen on somata an d apical dendrites with reduced labeling on basal dendrites. In CA2, differ ential rearrangement of all three alpha-subunits occurred. Moreover, there was layer-specific loss of alpha 1-subunit-immunoreactive interneurons in h ippocampus proper, whereas surviving interneurons exhibited extensive chang es in dendritic morphology. Throughout, expression patterns of beta 2,3- an d gamma 2-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 GAB A system.