Specific subunits of γ-aminobutyric acid (GABA)A receptors may be regulated differentially in animal models of temporal lobe epilepsy during the chronic stage. Although several subunits may be upregulated, other subunits may be downregulated in the hippocampal formation. The α5 subunit is of particular interest because of its relatively selective localization in the hippocampus and its potential role in tonic inhibition. In normal rats, immunolabeling of the α5 subunit was high in the dendritic layers of CA1 and CA2 and moderate in these regions of CA3. In chronic pilocarpine-treated rats displaying recurrent seizures, α5 subunit-labeling was substantially decreased in CA1 and nearly absent in CA2. Only slight decreases in immunolabeling were evident in CA3. In situ hybridization studies demonstrated that the α5 subunit mRNA was also strongly decreased in stratum pyramidale of CA1 and CA2. Thus, the alterations in localization of the α5 subunit peptide and its mRNA were highly correlated. The large decreases in labeling of the α5 subunit did not appear to be related to loss of pyramidal neurons in CA1 or CA2 since these neurons were generally preserved in pilocarpine-treated animals. No comparable decreases in labeling of the α2 subunit of the GABAA receptor were detected. These findings indicate that the α5 subunit of the GABAA receptor is capable of substantial and prolonged downregulation in remaining pyramidal neurons in a model of temporal lobe epilepsy. The results raise the possibility that presumptive extrasynaptic GABAA receptor subunits, such as the α5 subunit, may be regulated differently than synaptically located subunits, such as the α2 subunit, within the same brain regions in some pathological conditions. Hippocampus 2003;13:633–645. © 2003 Wiley-Liss, Inc.