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

Doctoral thesis English OPEN
Venzi, Marcello
  • Subject: Q1 | QR

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.
  • References (11)
    11 references, page 1 of 2

    Huguenard JR, Prince D a (1992) A novel T-type current underlies prolonged Ca(2+)-dependent burst firing in GABAergic neurons of rat thalamic reticular nucleus. J Neurosci 12:3804-3817.

    Jakus R, Graf M, Juhasz G, Gerber K, Levay G, Halasz P, Bagdy G (2003) 5-HT2C receptors inhibit and 5-HT1A receptors activate the generation of spike-wave discharges in a genetic rat model of absence epilepsy. Exp Neurol 184:964-972.

    Jallon P, Loiseau P, Loiseau J (2001) Newly diagnosed unprovoked epileptic seizures: presentation at diagnosis in CAROLE study. Coordination Active du Réseau Observatoire Longitudinal de l' Epilepsie. Epilepsia 42:464-475.

    Jia F, Yue M, Chandra D, Homanics GE, Goldstein P a, Harrison NL (2008) Isoflurane is a potent modulator of extrasynaptic GABA(A) receptors in the thalamus. J Pharmacol Exp Ther 324:1127-1135.

    Kehne JH, Baron BM, Carr AA, Chaney SF, Elands J, Feldman DJ, Frank RA, van Giersbergen PL, McCloskey TC, Johnson MP, McCarty DR, Poirot M, Senyah Y, Siegel BW, Widmaier C, Chaney F, Johnson P, Feldman J, Roussel M (1996) Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100,907 as a potent 5-HT2A antagonist with a favorable CNS safety profile. J Pharmacol Exp Ther 277:968-981.

    Lachance-Touchette P, Martin C, Poulin C, Gravel M, Carmant L, Cossette P (2010) Screening of GABRB3 in French-Canadian families with idiopathic generalized epilepsy. Epilepsia 51:1894-1897.

    Lam Y-W, Sherman SM (2007) Different topography of the reticulothalmic inputs to first- and higher-order somatosensory thalamic relays revealed using photostimulation. J Neurophysiol 98:2903-2909.

    Lam Y-W, Sherman SM (2011) Functional organization of the thalamic input to the thalamic reticular nucleus. J Neurosci 31:6791-6799.

    Lambert RC, Bessaïh T, Crunelli V, Leresche N (2014) The many faces of T-type calcium channels. Pflugers Arch 466:415-423.

    Pape HC, Budde T, Mager R, Kisvárday ZF (1994) Prevention of Ca(2+)-mediated action potentials in GABAergic local circuit neurones of rat thalamus by a transient K+ current. J Physiol 478 Pt 3:403-422.

  • Related Research Results (1)
  • Metrics
    views in OpenAIRE
    views in local repository
    downloads in local repository

    The information is available from the following content providers:

    From Number Of Views Number Of Downloads
    Online Research @ Cardiff - IRUS-UK 0 86
Share - Bookmark