ZEFV.htm

NR ZEFV

AU Freichel,C.

TI Untersuchung GABAerger Neurone im Piriformen Cortex und anderen Epilepsie-relevanten Gehirnregionen der Ratte in verschiedenen Modellen der Temporallappenepilepsie

QU Vet. med. Diss. Tierärztliche Hochschule Hannover, 2001

PT Dissertation

AB A deficit in GABAergic inhibition is hypothesisized to underlie human temporal lobe epilepsy. This disease rsults in complex-focal seizures, which commonly display resistance to pharmacological treatment. The piriform cortex (PC) is thought to be critically involved in the generation and propagation of seizure activity. Recently, a chronic loss of GABA-immunoreactive neurons in the central PC has been described in the amygdala-kindling model of temporal lobe epilepsy, indicating that GABA mediated mechanisms might be involved in this regard. Although GABAergic neurons in the PC have been investigated immunhistochemically for GABA and its synthesizing enzyme glutamic acid decarboxylase (GAD), the exppression pattern of GAD in the POC need to be further investgated. The brain contains at least two isoforms of GAD, termed GAD65 and GAD67, which differ in the level of expression among brain regions. In order to investigate the expression of mRNA encoding for GAD-Isoforms in the PC and other brain regions thought to be involved in epileptogenesis, two different protocols for in situt hybridization were established. Using npn-radioactively or radioactively labelled probes, no differences in the number of cells marked for GAD-mRNA were obvious. Therefore, non-radioactive in situ hybridization was utilized for further studies. Basal conditions revealed a higher number of GAD- and GABA-immunoreactive neurons in the majority of the investigated brain regions compared to cell counts obtained by in situ hybridization. This result was most striking in layer II of the PC, with immunoreactive neurons displaying a 10fold higher density of GABAergic neurons compared to in situ hybridization. Furthermore, possible alterations in the expression of GAD isoforms provoked by seizure activity were investigated. For this purpose a self-sustained status epilepticus was induced in female Wistar rats by administration of kainate and lithium-pilocarpine, respectively, which was terminated after 90 min with diazepam. All animals eerre perfused 8 h post application. An upregulation of GAD67 but not GAD65-mRNA was determined in granule cells of the hippocampus in both models. In the PC, seizure activity resulted in an upregulation of GAD-mRNA in layer II of the central PC, while the number of GAD and GABA positive neurons was decreased. In the amygdala, the hilus of the gyrus dentatus, and the substantia nigra pars re6iculata a decrease of GABAergic neurons was detected using in situ hybridization and immunhistochemistry. Finally, in parts of the substantia nigra pars reticulata and the central and posterior parts of the PC a marked neurodegeneration occurred. Possible chronic alterations in the expression og GAD-mRNA were investigated in the amygdala-kindling mode. Following 10 stimulated secondary generalized seizures, kindled animals were perfused 42 days after the last elicited convulsion to avoid transient effects related to the stimulation process. Neurons expressing GAD65-mRNA were decreased bilaterally in the basolateral amygdala, while neurons containing GAD67-mRNA were not significantly reduced. Cell counts in the PC, the hippocampal formation, and the substantia nigra pars reticulata revealed no significant changes compared to controls. The present data indicate that individual stages in the metabolism of GABA are differently regulated under basal and pathophysiological conditions. The results strongly suggest of combination of different histological techniques if alterations in the GABA system are investigated in animal models of temporal lobe epilepsy.

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