{"doi":"10.1101/2020.06.28.172460","title":"Post-ictal generalized EEG suppression and seizure-induced mortality are reduced by enhancing dorsal raphe serotonergic neurotransmission","abstract":"Abstract Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. A proposed risk marker for SUDEP is the duration of post-ictal generalized EEG suppression (PGES). The mechanisms underlying PGES are unknown. Serotonin (5-HT) has been implicated in SUDEP pathophysiology. Seizures suppress activity of 5-HT neurons in the dorsal raphe nucleus (DRN). We hypothesized that suppression of DRN 5-HT neuron activity contributes to PGES and increasing 5-HT neurotransmission or stimulating the DRN before a seizure would decrease PGES duration. Adult C57BL/6 and Pet1-Cre mice received EEG/EMG electrodes, a bipolar stimulating/recording electrode in the right basolateral amygdala, and either a microdialysis guide cannula or an injection of adeno-associated virus (AAV) allowing expression of channelrhodopsin2 plus an optic fiber into the DRN. Systemic application of the selective 5-HT reuptake inhibitor citalopram (20 mg/kg) decreased PGES duration from seizures induced during wake (n = 23) and NREM sleep (n = 13) whereas fluoxetine (20 mg/kg) pretreatment decreased PGES duration following seizures induced from wake (n = 11), but not NREM sleep (n = 9). Focal chemical (n = 6) or optogenetic (n = 8) stimulation of the DRN reduced PGES duration following kindled seizures and reduced morality following maximal electroshock seizures (n = 6) induced during wake. During PGES, animals exhibited immobility and suppression of EEG activity that was reduced by citalopram pretreatment. These results indicate that 5-HT and the DRN may regulate PGES and seizure-induced mortality. Highlights - PGES consistently follows seizures induced by amygdala stimulation in amygdala-kindled mice. - Seizure-induced dysregulation of 5-HT neurotransmission from the dorsal raphe nucleus may contribute to PGES. - Systemic administration of 5-HT enhancing drugs and stimulation of the DRN reduces PGES duration. - PGES is associated with post-ictal immobility in kindled mice that can be reduced by pretreatment with citalopram. - Recovery of EEG frequencies to baseline occurs in a stepwise manner with the lowest frequencies recovering first.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127008,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9601,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":575079,"name":"Katelyn G. Joyal","orcid":"0000-0002-2949-6105","position":1,"is_corresponding":false},{"id":575463,"name":"Jonathan W. Chou","orcid":null,"position":2,"is_corresponding":false},{"id":575080,"name":"Rui Li","orcid":"0000-0002-7339-7526","position":3,"is_corresponding":false},{"id":575464,"name":"Kimberly M. Vencer","orcid":null,"position":4,"is_corresponding":false},{"id":537859,"name":"Gordon F. Buchanan","orcid":"0000-0003-2371-4455","position":5,"is_corresponding":false},{"id":575078,"name":"Alexandra N. Petrucci","orcid":"0000-0001-7403-9854","position":0,"is_corresponding":true}],"reference_count":91,"raw_metadata":null,"created_at":"2026-07-18T23:15:27.226519Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}