Expression of GABAA receptor subunit mRNAs in hippocampal pyramidal and granular neurons in the kindling model of epileptogenesis: an in situ hybridization study

Abstract

Expression of GABA-A receptor subunit in mRNAs in hippocampal pyramidal and granular neurons in the kindling model of epileptogenesis: an in situ hybridization study. Kamphuis, W.; de Rijk, T.C.; Lopes da Silva, F.H. Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Accepted 24 January 1995 AbstractTo investigate the molecular changes underlying kindling epileptogenesis in the rat hippocampus, the expression levels of the genes encoding for 13 different y-aminobutyric acid type-A receptor (GABAAR) subunits were measured in hippocampal principal neurons using in situ hybridization techniques and semi-quantitative analysis of the autoradiograms. Schaffer collateral-commissural pathway kindled rats were investigated at three different stages of kindling acquisition, at 24 h after the last seizure and at long-term (28 days) after termination of kindling stimulations. Changes were distinct for the different subunits in the three analyzed regions (CA1, CA3, fascia dentata) and also different for the various kindling stages. In all hippocampal areas at the early phases of kindling epileptogenesis, before the appearance of generalized seizures, an increase was found of those transcripts that constituted the majority of the expressed variants in control animals (al, a2, a4, /31, /32, /33, y2/y2L mRNA). In these stages, the increased levels of different variants in the granular neurons of the fascia dentata were more pronounced when compared to the pattern of changes in pyramidal cells of CA1 and CA3. In fully kindled animals, the expression levels of several subunits returned to control levels, whereas/33 and y2/y2L mRNA expression was still significantly enhanced in all areas. At long-term, few changes were encountered. The long-splice variant of 3,2 was decreased within pyramidal and granular neurons while the total level of y2 mRNA was not different from controls. The increased GABAAR subunit expression in the fascia dentata may underly the reported increased GABAAR ligand binding and the increased GABA mediated inhibition. However, the decreased GABAAR binding and the attenuation of GABAergic inhibition in CA1, could not be explained by a decrement of receptor subunit expression.

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

“…According to these experiments, the augmented inhibition found in the epileptic tissue is however decreased by the Zn 2+ that is released from aberrantly sprouted mossy fiber terminals of granule cells during seizures. Evidence has also been obtained for selective changes in receptor subunit expression in animal models of TLE (Kamphuis et al, 1994(Kamphuis et al, , 1995Rice et al, 1996;Brooks-Kayal et al, 1998).…”

Plasticity in GABAAReceptor Subunit mRNA Expression by Hypothalamic Magnocellular Neurons in the Adult Rat

“…To date, such studies have concentrated on developmental regulation, including changes during aging (MacLennan et al, 1991;Poulter et al, 1993;Fritschy et al, 1994;Gutierrez et al, 1994;Mathews et al, 1994), and examined the response of GABA A receptor expression and function in adults to a variety of allosteric GABA A receptor modulators (Kang and Miller, 1991;Montpied et al, 1991;Primus and Gallager, 1992;Mhatre et al, 1993;Tseng et al, 1994) as well as excitatory and inhibitory amino acids (Kim et al, 1993;Mhatre and Ticku, 1994;Zhu et al, 1995;Fénelon and Herbison, 1996). Further work has examined GABA A receptor expression in pathological states such as epilepsy (Kokaia et al, 1994;Kamphuis et al, 1995), Huntington's disease (Faull et al, 1993), and chronic stress (Montpied et al, 1993). Although these studies clearly have relevance in understanding the developmental and pathophysiological roles of GABA transmission in the brain, surprisingly little evidence exists for changes in GABA A receptor expression within a physiological context in the adult brain.…”

Isozyme specific changes in the expression of protein kinase C isozyme (α-ζ) genes in the hippocampus of rats induced by kindling epileptogenesis

“…In order to gain insight in the relative abundance of the different PKC transcripts within the hippocampus in control animals, the obtained extinction values were corrected for the differences in specific activity of the probe used for the in situ hybridization and for the different film exposure durations [9]. For each probe, the correction factor for CA1, CA3 and fascia dentata was identical.…”

“…The behavioural and EEG characteristics of kindling development, initiated by tetanic stimulations to the Schaffer collateral/commissural fibers in the dorsal hippocampus, have been presented before [9,13]. The expression of PKC mRNAs was studied in four groups of animals that were sacrificed at different stages of kindling.…”

“…However, the reduction of GABAergic inhibition is associated with only a small reduction in the binding of GABAA-receptor ligands [32], and is even paralleled by an unexpected increase of the expression levels of genes that encode for the subunits of the GABAA-receptor [9]. These confounding results led us to consider the possibility that the diminished GABAh-rece ptor function in kindled tissue may be a consequence of modifications in the mechanisms that regulate the activity of this receptor, particularly phosphorylation conditions.…”