5-HT2A/2C receptor modulation\ud of absence seizures and\ud characterization of the GHB-model

Doctoral thesis English OPEN
Venzi, Marcello
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Absence seizures (ASs) are non-convulsive epileptic events which are common in pediatric and juvenile epilepsies. They consist of EEG generalized spike-and-wave-discharges (SWDs) accompanied by an impairment of consciousness and are expressed within the thalamocortical network. This thesis initially focused on investigating the modulation of ASs by two serotonin receptors (5-HTRs), 5-HT2A and 5-HT2C, in a polygenic (i.e. Genetic Absence Epilepsy Rats from Strasbourg, GAERS) and a pharmacological (i.e. γ-hydroxybutyrate, GHB) model of ASs. It was found that, in GAERS, pharmacological activation of 5-HT2A/CRs blocked ASs, whereas 5-HT2AR antagonists increased seizure length. However, experiments on the GHB-model revealed that GHB induced not only ASs but also a period of sedation/hypnosis, a behavioural state that had been neglected in the literature. Thus, the rest of this thesis was devoted to further characterizing the GHB-model. The main result was that GHB-elicited ASs can be distinguished at the level of both EEG and behaviour. In vivo characterization of thalamic firing during GHB-elicited ASs and hypnosis via silicon probes in freely moving animals revealed that both states were accompanied by a decrease in firing rate. In particular, contrary to what was predicted by in vitro and in vivo experiments under neurolept anaesthesia, T-type Ca2+ channel-dependent burst firing in thalamic neurons was found in <10% of spike-and-wave complexes of SWDs. The prevalent activity of nucleus reticularis thalami neurons during ASs was either silence or tonic firing. Indeed, thalamic application of the potent T-type channel antagonist, TTAP-2, by reverse microdialysis did not affect GHB-elicited ASs. Finally, the development of an algorithm to classify GHB-elicited ASs demonstrated that the spectral properties of SWDs can be used to discriminate hypnosis and SWDs. Moreover, spectral coherence can be used in different experimental models of ASs to characterize SWDs according to their waveform regularity.
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