Journal article
Serotonin neurones have anti-convulsant effects and reduce seizure-induced mortality
The Journal of physiology, Vol.592(19), pp.4395-4410
10/01/2014
DOI: 10.1113/jphysiol.2014.277574
PMCID: PMC4215784
PMID: 25107926
Abstract
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. Defects in central control of breathing are important contributors to the pathophysiology of SUDEP, and serotonin (5-HT) system dysfunction may be involved. Here we examined the effect of 5-HT neurone elimination or 5-HT reduction on seizure risk and seizure-induced mortality. Adult Lmx1b(f/f/p) mice, which lack >99% of 5-HT neurones in the CNS, and littermate controls (Lmx1b(f/f)) were subjected to acute seizure induction by maximal electroshock (MES) or pilocarpine, variably including electroencephalography, electrocardiography, plethysmography, mechanical ventilation or pharmacological therapy. Lmx1b(f/f/p) mice had a lower seizure threshold and increased seizure-induced mortality. Breathing ceased during most seizures without recovery, whereas cardiac activity persisted for up to 9 min before terminal arrest. The mortality rate of mice of both genotypes was reduced by mechanical ventilation during the seizure or 5-HT2A receptor agonist pretreatment. The selective serotonin reuptake inhibitor citalopram reduced mortality of Lmx1b(f/f) but not of Lmx1b(f/f/p) mice. In C57BL/6N mice, reduction of 5-HT synthesis with para-chlorophenylalanine increased MES-induced seizure severity but not mortality. We conclude that 5-HT neurones raise seizure threshold and decrease seizure-related mortality. Death ensued from respiratory failure, followed by terminal asystole. Given that SUDEP often occurs in association with generalised seizures, some mechanisms causing death in our model might be shared with those leading to SUDEP. This model may help determine the relationship between seizures, 5-HT system dysfunction, breathing and death, which may lead to novel ways to prevent SUDEP.
Details
- Title: Subtitle
- Serotonin neurones have anti-convulsant effects and reduce seizure-induced mortality
- Creators
- Gordon F Buchanan - Department of Neurology, Yale University School of Medicine, New Haven, CT, 06520, USA Veteran's Affairs Medical Center, West Haven, CT, 06516, USA gordon.buchanan@yale.eduNicholas M Murray - Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USAMichael A Hajek - Department of Neurology, Yale University School of Medicine, New Haven, CT, 06520, USAGeorge B Richerson - Department of Neurology, Yale University School of Medicine, New Haven, CT, 06520, USA Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA Veteran's Affairs Medical Center, Iowa City, IA, 52242, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of physiology, Vol.592(19), pp.4395-4410
- Publisher
- England
- DOI
- 10.1113/jphysiol.2014.277574
- PMID
- 25107926
- PMCID
- PMC4215784
- ISSN
- 0022-3751
- eISSN
- 1469-7793
- Grant note
- UL1 TR000142 / NCATS NIH HHS K08 NS069667 / NINDS NIH HHS P20 NS076916 / NINDS NIH HHS R01 HD052772 / NICHD NIH HHS U01 NS090414 / NINDS NIH HHS
- Language
- English
- Date published
- 10/01/2014
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Neurosurgery
- Record Identifier
- 9984019523902771
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