Abstract
The parahippocampal areas including the subiculum, pre- and parasubiculum, and notably the entorhinal cortex (EC) are intimately involved in the generation of limbic seizures in temporal lobe epilepsy. We investigated changes in the expression of 10 major GABAA receptor subunit mRNAs in subfields of the ventral hippocampus, ventral subiculum, EC, and perirhinal cortex (PRC) at different intervals (1, 8, 30, and 90 days) after kainic acid (KA)-induced status epilepticus priming epileptogenesis in the rat. The most pronounced and ubiquitous changes were a transient (24 h after KA only) down-regulation of γ2 mRNA and lasting decreases in subunit α5, β3, and δ mRNAs that were prominent in all hippocampal and parahippocampal areas. In the subiculum similarly as in sectors CA1 and CA3, levels of subunit α1, α2, α4, and γ2 mRNAs decreased transiently (1 day after KA-induced status epilepticus). They were followed by increased expression of subunit α1 and α3 mRNAs in the dentate gyrus (DG) and sectors CA1 and CA3, and subunit α1 also in the EC layer II (30 and 90 days after KA). We also observed sustained overexpression of subunits α4 and γ2 in the subiculum and in the Ammon’s horn. Subunit γ2 mRNA was also increased in sector CA1 at the late intervals after KA. Taken together, our results suggest distinct regulation of mRNA expression for individual GABAA receptor subunits. Especially striking was the wide-spread down-regulation of the often peri- or extrasynaptically located subunits α5 and δ. These subunits are often associated with tonic inhibition. Their decrease could be related to decreased tonic inhibition or may merely reflect compensatory changes. In contrast, expression of subunit α4 that may also mediate tonic inhibition when associated with the δ-subunit was significantly upregulated in the DG and in the proximal subiculum at late intervals. Thus, concomitant up-regulation of subunit γ2, α1 and α4 mRNAs (and loss in δ-subunits) ultimately indicates significant rearrangement of GABAA receptor composition after KA-induced seizures.
Highlights
Temporal lobe epilepsy (TLE) is the most common and difficult to treat form of focal epilepsies
To elucidate possible changes in GABAergic transmission in parahippocampal areas we investigated changes in GABAA receptor subunit expression in the ventral hippocampus including the subiculum and the entorhinal and perirhinal cortices
We observed significantly increased expression of γ2 mRNA in the granule cell layer of the dentate gyrus (DG), in layer II of the entorhinal cortex (EC), and in the perirhinal cortex (PRC)
Summary
Temporal lobe epilepsy (TLE) is the most common and difficult to treat form of focal epilepsies. Neurodegeneration and epilepsy-induced neurochemical changes were found in areas closely associated with the hippocampus, such as the subiculum (Andrioli et al, 2007) and the entorhinal cortex (EC; Du et al, 1993; Bartolomei et al, 2005) These brain regions may be intimately involved in seizure propagation in human TLE (Cohen et al, 2002; Wozny et al, 2005; Fabo et al, 2008; Huberfeld et al, 2011) and in animal models of TLE (Knopp et al, 2005; de Guzman et al, 2006; Kumar and Buckmaster, 2006).
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