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1.
Respir Physiol Neurobiol ; 170(2): 173-82, 2010 Feb 28.
Article in English | MEDLINE | ID: mdl-20040383

ABSTRACT

Rett syndrome is a neurodevelopmental disease accompanied by complex, disabling symptoms, including breathing symptoms. Because Rett syndrome is caused by mutations in the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2), Mecp2-deficient mice have been generated as experimental model. Males of Mecp2-deficient mice (Mecp2(-/y)) breathe normally at birth but show abnormal respiratory responses to hypoxia and hypercapnia from postnatal day 25 (P25). After P30, Mecp2(-/y) mice develop breathing symptoms reminiscent of Rett syndrome, aggravating until premature death at around P60. Using plethysmography, we analyzed the sighs and the post-sigh breathing pattern of unrestrained wild type male mice (WT) and Mecp2(-/y) mice from P15 to P60. Sighs are spontaneous large inspirations known to prevent lung atelectasis and to improve alveolar oxygenation. However, Mecp2(-/y) mice show early abnormalities of post-sigh breathing, with long-lasting post-sigh apnoeas, reduced tidal volume when eupnoea resumes and lack of post-sigh bradypnoea which develop from P15, aggravate with age and possibly contribute to breathing symptoms to come.


Subject(s)
Hypercalcemia/complications , Hypoxia/complications , Methyl-CpG-Binding Protein 2/deficiency , Respiratory System Abnormalities/physiopathology , Rett Syndrome/physiopathology , Age Factors , Animals , Animals, Newborn , Apnea/genetics , Apnea/physiopathology , Disease Models, Animal , Hypercalcemia/genetics , Hypoxia/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Plethysmography , Respiration/genetics , Respiratory Mechanics/genetics , Respiratory System Abnormalities/genetics , Rett Syndrome/genetics , Tidal Volume/genetics
2.
J Neurosci ; 20(12): 4646-56, 2000 Jun 15.
Article in English | MEDLINE | ID: mdl-10844034

ABSTRACT

In rodent neonates, the neurotransmitter serotonin (5-HT) modulates the activity of both the medullary respiratory rhythm generator and the cervical phrenic motoneurons. To determine whether 5-HT also contributes to the maturation of the respiratory network, experiments were conducted in vitro on the brainstem-spinal cord preparation of neonatal mice originating from the control strain (C3H) and the monoamine oxidase A-deficient strain, which has a brain perinatal 5-HT excess (Tg8). At birth, the Tg8 respiratory network is unable to generate a respiratory pattern as stable as that produced by the C3H network, and the modulation by 5-HT of the network activity present in C3H neonates is lacking in Tg8 neonates. In addition, the morphology of the phrenic motoneurons is altered in Tg8 neonates; the motoneuron dendritic tree loses the C3H bipolar aspect but exhibits an increased number of spines and varicosities. These abnormalities were prevented in Tg8 neonates by treating pregnant Tg8 dams with the 5-HT synthesis inhibitor p-chlorophenylalanine or a 5-HT(2A) receptor antagonist but were induced in wild-type neonates by treating C3H dams with a 5-HT(2A) receptor agonist. We conclude that 5-HT contributes, probably via 5-HT(2A) receptors, to the normal maturation of the respiratory network but alters it when present in excess. Disorders affecting 5-HT metabolism during gestation may therefore have deleterious effects on newborns.


Subject(s)
Brain/physiology , Medulla Oblongata/physiology , Monoamine Oxidase/metabolism , Motor Neurons/physiology , Phrenic Nerve/physiology , Serotonin/physiology , Spinal Cord/physiology , Animals , Animals, Newborn , Dendrites/physiology , Female , Fetus , Fluorobenzenes/pharmacology , Mice , Mice, Inbred C3H , Mice, Knockout , Mice, Transgenic , Monoamine Oxidase/deficiency , Monoamine Oxidase/genetics , Motor Neurons/cytology , Patch-Clamp Techniques , Phenols/pharmacology , Phrenic Nerve/cytology , Pregnancy , Receptor, Serotonin, 5-HT2A , Receptors, Serotonin/drug effects , Receptors, Serotonin/physiology , Respiratory Mechanics/physiology , Serotonin Antagonists/pharmacology
3.
Neurosci Lett ; 261(1-2): 41-4, 1999 Feb 12.
Article in English | MEDLINE | ID: mdl-10081922

ABSTRACT

Developmental changes in levels of serotonin, L-tryptophan and 5-hydroxyindol acetic acid (5-HIAA) were measured by high pressure liquid chromatography (HPLC) in the forebrain, brainstem and cervical cord of fetal, neonatal and adult mice from the wild strain C3H and the transgenic strain Tg8, created from the C3H line by the disruption of the gene encoding monoamine oxidase A. The results indicated that the absence of monoamine oxidase A activity in Tg8 mice results in abnormally high 5-hydroxytryptamine (5-HT) levels in all the central nervous structures and at all the studied developmental ages. Since serotonin levels were 4-5 times larger in Tg8 than in C3H mice at gestational day 20, comparing the central network function at birth of C3H and Tg8 neonates should shed some light on the role of serotonin in prenatal network maturation.


Subject(s)
Fetus/enzymology , Monoamine Oxidase/genetics , Monoamine Oxidase/metabolism , Serotonin/metabolism , Animals , Brain Stem/embryology , Brain Stem/enzymology , Gene Expression Regulation, Developmental , Gene Expression Regulation, Enzymologic , Hydroxyindoleacetic Acid/metabolism , Mice , Mice, Inbred C3H , Mice, Transgenic , Prosencephalon/embryology , Prosencephalon/enzymology , Spinal Cord/embryology , Spinal Cord/enzymology
4.
J Physiol ; 466: 367-81, 1993 Jul.
Article in English | MEDLINE | ID: mdl-7692042

ABSTRACT

1. Experiments were performed on anaesthetized newborn rats (aged 3-10 days) to know whether an increase in central serotonin levels might favour the occurrence of obstructive apnoeas as previously suggested by in vitro results from our group. 2. The levels of serotonin (5-HT), its precursor 5-hydroxytryptophan (5-HTP) and its metabolite, 5-hydroxyindole-acetic acid (5-HIAA), were analysed in cerebrospinal fluid samples collected at the level of the obex prior to and after intraperitoneal injection of L-tryptophan (50 mg kg-1) in sixty-eight anaesthetized newborn rats (control rats prior to injection and injected rats 15, 30 and 45 min after the injection). A significant increase in 5-HT and 5-HTP levels occurred 30 min after the injection, attesting to the activation of 5-HT biosynthesis. 3. The EMG activity of both the genioglossus and the diaphragm was recorded before and after L-tryptophan load (50 mg kg-1) in twenty-two newborn rats. After the injection of L-tryptophan, the amplitude of the integrated genioglossus activity decreased, or was even abolished, either during a few respiratory cycles or for long periods in twenty-one out of twenty-two animals. Recovery of the genioglossus activity occurred within 45-60 min. 4. The thoracic respiratory movements and the resulting upper airway pressure changes were recorded before and after L-tryptophan injection (50 mg kg-1) in sixty-two animals. In some litters (n = 7), most of the animals (21/25) displayed, within 20-40 min of the injection, recurrent episodes of obstructive apnoea often followed by central ones. These respiratory difficulties became severe and drastic, and led in two instances to respiratory distress and death. Lower doses of L-tryptophan (10 mg kg-1) did not induce any respiratory disorders unless these were potentiated by pargyline treatment (50 mg kg-1, n = 7). The obstructive apnoeas liable to occur after an L-tryptophan load (50 mg kg-1) were prevented by blocking the 5-HT receptor with methysergide (50 mg kg-1, n = 5) or by blocking the 5-HT biosynthesis by applying p-chlorophenylalanine (PCPA) pretreatment at birth (300 mg kg-1, n = 7). In other litters (n = 6), none of the eighteen newborn rats tested were affected by L-tryptophan, however, In five young adult rats, L-tryptophan again had no effect.4+ e


Subject(s)
Serotonin/metabolism , Sleep Apnea Syndromes/etiology , 5-Hydroxytryptophan/cerebrospinal fluid , Animals , Animals, Newborn , Electromyography , Humans , Hydroxyindoleacetic Acid/cerebrospinal fluid , Infant , Injections, Intraperitoneal , Rats , Rats, Sprague-Dawley , Respiratory Muscles/drug effects , Respiratory Muscles/physiopathology , Serotonin/cerebrospinal fluid , Sleep Apnea Syndromes/cerebrospinal fluid , Sleep Apnea Syndromes/physiopathology , Sudden Infant Death/etiology , Tryptophan/administration & dosage
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