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- COMPUTER MODELING
- DIFFERENTIAL GENE EXPRESSION
Summary: Purpose: We present results obtained by computer modeling of the thalamic network and differential gene expression analysis in a rat strain with absence epilepsy, the genetic absence epilepsy rat from Strasbourg (GAERS).
Methods: (a) Computer modeling used equations from the Hodgking–Huxley model with a circuit of 13 reticular thalamic (nRt) and 39 thalamocortical (TC) neurons; (b) gene-expression analysis using differential mRNA display (DD), in situ hybridization, Northern blotting, and competitive reverse transcriptase–polymerase chain reaction (RT-PCR).
Results: (a) Computer modeling showed an increased network synchrony in the thalamic circuit as the value of conductance of low-voltage activated calcium channel (LVACC) is increased. (b) Using differential mRNA display, a 40% upregulation of the H-ferritin mRNA in the hippocampus was demonstrated. Looking for some candidate genes of the VACC family, no difference was found in the α1G mRNA expression between GAERS and control animals, whereas a decreased expression of the α1E subunit was observed in the cerebellum and the brainstem of the GAERS. This phenomenon was not observed in young animals when the epileptic phenotype is not expressed.
Conclusions: The use of computer modeling appeared to be an efficient way to evaluate the impacts of electrophysiologic findings in vivo from single cells on an entire circuit. No clear single gene defect was revealed so far in GAERS. More information could arise from linkage analysis. However, some brain structures like hippocampus or cerebellum classically not known to be involved in the production of absence spike-and-wave discharges could in fact participate in the development of this phenotype.
In experimental conditions, the genetic absence epilepsy rats from Strasbourg (GAERS) resemble humans with absence epilepsy (1). These animals exhibit absence-like seizures occurring spontaneously, as abrupt behavioral arrests, staring, and clonic twitching of the vibrissae, associated with high-amplitude spike-and-wave discharges (SWDs) at 7–9 Hz on the EEG. As in humans, (a) the illness is inherited, (b) the onset of seizures is age dependent, (c) seizure occurrence is maximal during phases of quiet wakefulness, (d) SWDs are suppressed by drugs effective against childhood absence epilepsy, and (e) SWDs were demonstrated to involve the lateral thalamic nuclei.
The hypothesis that the mechanisms of the thalamocortical synchronization could be implicated in the generation of spontaneous SWDs has been extensively investigated (2). At the molecular level, electrophysiologic studies have showed that a rhythmic sequence of γ-aminobutyric acid type B (GABAB) inhibitory postsynaptic potential (IPSP) and low-threshold calcium potential could be involved in the intrinsic pacemaker oscillations by which low-frequency oscillation of the membrane potential and associated burst firing can be produced by thalamocortical neurons (3,4). Many studies have therefore analyzed the properties of the GABAB receptor and T-type calcium current in the GAERS. Recently, however, some of the same researchers have cast some doubts on the exact mechanism of these oscillations during SWDs (5). Concerning GABAB, the results were contradictory, as some authors found no differences in density and affinity for this receptor in GAERS versus Wistar rats (6), whereas others find a twofold increase in affinity (7). Conversely, a selective increase in low-threshold calcium current conductance was recorded in the reticular thalamic nucleus of the GAERS (8), but this difference is detected considerably earlier (P11–P18) than the full development of SWDs (P30–P40).
In the present article we review, in light of more recent data from the current literature, results obtained on this model in our laboratory using (a) computer modeling to evaluate the impact of electrophysiologic findings from single units on the thalamic circuit; (b) differential gene expression analysis to see if the candidate genes or others are altered in this model. The details of these works have been previously published elesewhere (9–11).