Authors :
Presenting Author: Hayet Kouchi, PhD – Lyon Neurosciences Research Center (INSERM U1028, UMR 5292, Lyon 1 University)
Jonathon Smith, PhD – Lyon Neuroscience Research Center, Inserm U1028, CNRS UMR5292, Lyon 1 University; Beatrice Georges, na – Lyon Neuroscience Research Center, Inserm U1028, CNRS UMR5292, Lyon 1 University; Laurent Bezin, PhD – Lyon Neuroscience Research Center, Inserm U1028, CNRS UMR5292, Lyon 1 University; Sylvain Rheims, MD, PhD – Lyon Neuroscience Research Center, Inserm U1028, CNRS UMR5292, Lyon 1 University
Rationale:
The 5HT receptor type 2C (5-HT2C) is implicated in the hyperexcitability of neuronal networks that underlies epilepsy. More notably, knockout 5-HT2C mice experience fatal spontaneous seizure, and, in line with the implication of this receptor in the regulation of breathing, 5-HT2C may play a key role in the susceptibility to seizure-related fatal apnea. In the pilocarpine model of temporal lobe epilepsy (TLE), once rats present with spontaneous seizures, they showed ventilatory abnormalities during the inter-ictal period, associated with alterations of brainstem 5-HT transmission. However, TLE rats do not show seizure-related deaths. Our objective was to investigate the relation between epilepsy-related ventilatory alterations during the inter-ictal period, risk of death, and 5HT2C in the pilocarpine model of TLE.
Methods: At an age of seven weeks, 31 Sprague Dawley male rats underwent pilocarpine induced-
status epilepticus (
SE) (350 mg/kg,
i.p.) for 2 hours before it was stopped with diazepam. Thirteen rats were used as the control group. At 18 weeks post-
SE, rats were separated into two groups with three controls, and ten TLE rats were used for RTqPCR quantification of RNAm copies coding for brainstem enzyme of 5-HT synthesis and 5-HT reuptake: TPH2, SERT, respectively and 5-HT2C. The remaining rats were bilaterally implanted with cerebral electrodes within parietal and hippocampal regions. At 19-22 weeks post-
SE, rats are placed inside a whole-body plethysmography chamber to measure video-EEG and ventilation during 30 minutes and then for 2 hours after SB242084-administration (2mg/kg,
s.c.), a specific antagonist of 5-HT2C
Results: In line with our previous data, under basal conditions, interictal ventilation of TLE rats decreased by 20
± 5% compared to controls (P=0.01). The level of transcripts of TPH2, SERT, 5-HT2C of TLE rats are overexpressed compared to controls. Before administration of SB242084, we observed that 21% of TLE rats have presented with non-fatal seizures during the period of recording compared to 57% of them after SB242084 is injected. After administration of SB242084, both control and TLE rats showed abnormal ventilation (p< 0.001 and p=0.006, respectively) and alteration of breathing stability (number of apnea post-sigh and sigh). However, we did not observe a significant aggravation of the abnormal respiratory pattern of TLE rats. In contrast, the negative effect of SB242084 on respiratory frequency was greater in controls than in TLE rats (p< 0.001), whereas the duration of post-sigh apneas was shorter in TLE rats than in controls (p=0.001).Conclusions:
These findings show that 5-HT2C may partially contribute to epileptic phenotype and ventilatory pattern of EPI rats but its overexpression does not mediate the adaptative processes against fatal outcome in EPI rats and may not be a pertinent target to prevent epilepsy-related respiratory dysfunction
Funding: HK was funded by the French Chapter of the ILAE and ANR Sero-DRAVET. JS was funded by ERANET-NEURON AUTONOMIC.