Journal article
Transgenic Mice Lacking Serotonin Neurons Have Severe Apnea and High Mortality during Development
The Journal of neuroscience, Vol.29(33), pp.10341-10349
08/19/2009
DOI: 10.1523/JNEUROSCI.1963-09.2009
PMCID: PMC2755228
PMID: 19692608
Abstract
Central serotonin (5-HT) neurons modulate many vital brain functions, including respiratory control. Whether breathing depends critically on 5-HT neurons, or whether their influence is excitatory or inhibitory, remains controversial. Here we show that neonatal
Lmx1b
flox/flox;ePet-Cre
/+
mice (also called
Lmx1b
f/f/p
mice), which selectively lack serotonin neurons, display frequent and severe apnea lasting as long as 55 s. This was associated with a marked decrease in ventilation to less than one-half of normal. These respiratory abnormalities were most severe during the postnatal period, markedly improving by the time the pups were 2–4 weeks old. Despite the severe breathing dysfunction, many of these mice survived, but there was a high perinatal mortality, and those that survived had a decrease in growth rate until the age at which the respiratory defects resolved. Consistent with these
in vivo
observations, respiratory output was markedly reduced in isolated brainstem–spinal cord preparations from neonatal
Lmx1b
f/f/p
mice and completely blocked in perfused brain preparations from neonatal rats treated with selective antagonists of 5-HT
2A
and neurokinin 1 (NK-1) receptors. The ventilatory deficits in neonatal
Lmx1b
f/f/p
mice were reversed
in vitro
and
in vivo
with agonists of 5-HT
2A
and/or NK-1 receptors. These results demonstrate that ventilatory output in the neonatal period is critically dependent on serotonin neurons, which provide excitatory drive to the respiratory network via 5-HT
2A
and NK-1 receptor activation. These findings provide insight into the mechanisms of sudden infant death syndrome, which has been associated with abnormalities of 5-HT neurons and of cardiorespiratory control.
Details
- Title: Subtitle
- Transgenic Mice Lacking Serotonin Neurons Have Severe Apnea and High Mortality during Development
- Creators
- Matthew R Hodges - Departments of Neurology and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510Mackenzie Wehner - Departments of Neurology and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510Jason Aungst - Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke–National Institutes of Health, Bethesda, Maryland 20892-2540, andJeffrey C Smith - Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke–National Institutes of Health, Bethesda, Maryland 20892-2540, andGeorge B Richerson - Departments of Neurology and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.29(33), pp.10341-10349
- Publisher
- Society for Neuroscience
- DOI
- 10.1523/JNEUROSCI.1963-09.2009
- PMID
- 19692608
- PMCID
- PMC2755228
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Language
- English
- Date published
- 08/19/2009
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Neurosurgery
- Record Identifier
- 9984017175702771
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