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Iron is an essential element for plants as well as other organisms, functioning in various cellular processes, including respiration, chlorophyll biosynthesis, and photosynthesis. Plants take up iron from soil in which iron solubility is extremely low especially under aerobic conditions at high-pH range. Therefore, plants have evolved efficient iron-uptake mechanisms. Because iron is prone to being precipitated and excess ionic iron is cytotoxic, plants also have sophisticated internal iron-transport mechanisms. These transport mechanisms comprise iron chelators including nicotianamine, mugineic acid family phytosiderophores and citrate, and various types of transporters of these chelators, iron-chelate complexes, or free iron ions. To maintain iron homeostasis, plants have developed mechanisms for regulating gene expression in response to iron availability. Expression of various genes involved in iron uptake and translocation is induced under iron deficiency by transcription factor networks and is negatively regulated by the ubiquitin ligase HRZ/BTS. This response is deduced to be mediated by cellular iron sensing as well as long-distance iron signaling. The ubiquitin ligase HRZ/BTS is a candidate intracellular iron sensor because it binds to iron and zinc, and its activity is affected by iron availability. The iron-excess response of plants is thought to be partially independent of the iron-deficiency response. In this review, we summarize and discuss extant knowledge of plant iron transport and its regulation., (Copyright © 2018. Published by Elsevier Inc.)

Endocannabinoids (ECs) are bioactive lipid mediators acting on two distinct cannabinoid receptors (CB1 and CB2), which are ubiquitously expressed in many tissues including the respiratory system. Despite numerous experimental data showing that cannabinomimetics influence respiration, the role of endogenously produced ECs in respiratory control has not been verified yet. Pulse oximetry was used in the present study to directly measure changes in respiratory parameters during elevation of EC levels. The cannabinoid reuptake inhibitor AM-404 (10mgkg -1 , i.v.), but not its vehicle, induced a transient reduction of respiratory rate with a concomitant depression of arterial oxygen saturation and increase in breath distension in wild-type mice. In contrast, CB1 knock-out mice showed no alteration in any of these parameters upon administration of AM-404. Our results imply that the EC system has an important role in the physiological control of respiration by modulating the respiratory rate and consequently influencing arterial oxygen saturation. Furthermore, this mechanism is entirely dependent on CB1 receptors., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Prenatal nicotine exposure alters breathing and ventilatory responses to stress through stimulation of nicotine acetylcholine receptors (nAChRs). We tested the hypothesis that α4-containing nAChRs are involved in mediating the effects of prenatal nicotine exposure on ventilatory and metabolic responses to intermittent mild asphyxia (MA). Using open-flow plethysmography, we measured ventilation (V̇(E)) and rate of O2 consumption ( V̇(O2)) of wild-type (WT) and α4-knock-out (KO) mice, at postnatal (P) days 1-2 and 7-8, with and without prenatal nicotine exposure (6 mg kg(-1) day(-1) beginning on embryonic day 14). Mice were exposed to seven 2 min cycles of mild asphyxia (10% O2 and 5% CO2), each interspersed with 2 min of air. Compared to WT, α4 KO mice had increased air V̇(E) and V̇(O2) at P7-8, but not P1-2. Irrespective of age, genotype had no effect on the hyperventilatory response (increase in V̇(E)/V̇(O2)) to MA. At P1-2, nicotine suppressed air V̇(E) and V̇(O2) in both genotypes but did not affect the hyperventilatory response to MA. At P7-8 nicotine suppressed air V̇(E) and V̇(O2) of only α4 KO's but also significantly enhanced V̇(E) during MA (nearly double that of WT; p<0.001). This study has revealed complex effects of α4 nAChR deficiency and prenatal nicotine exposure on ventilatory and metabolic interactions and responses to stress., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Marfan syndrome (MFS) is a genetic disorder caused by mutations in the FBN1 gene that codifies for fibrilin-1. MFS affects elastic fiber formation and the resulting connective tissue shows abnormal tissue laxity and organization. Although an increased prevalence of obstructive sleep apnea among patients with MFS has been described, the potential effects of this genetic disease on the collapsible properties of the upper airway are unknown. The aim of this study was to assess the collapsible properties of the upper airway in a mouse model of MFS Fbn1((C1039G/+)) that is representative of most of the clinical manifestations observed in human patients. The upper airway in wild-type and Marfan mice was cannulated and its critical pressure (Pcrit) was measured in vivo by increasing the negative pressure through a controlled pressure source. Pcrit values from MFS mice were higher (less negative) compared to wild-type mice (-3.1±0.9cmH2O vs. -7.8±2.0cm H2O) suggesting that MFS increases the upper airway collapsibility, which could in turn explain the higher prevalence of OSA in MFS patients., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A number of distinct cuproproteins of the mitochondrial inner membrane are required for the assembly of cytochrome oxidase (COX), thought to function in a "bucket brigade" fashion to provide copper to the Cu(A) and Cu(B) sites. In yeast, the loss of two these proteins, Sco1p and Cox11p, leads to respiratory deficiency and a specific inability to survive exposure to hydrogen peroxide (H(2)O(2)). Using a quantitative assay, we have identified subtle differences in the peroxide-sensitive phenotypes between sco1 and cox11 mutant strains. Interestingly, the peroxide sensitivity of the sco1 null strain can be suppressed by overexpressing either SCO2 or COX11, although overexpression of neither SCO1 nor SCO2 can rescue the cox11 null strain. We also find that overexpression of either CTT1, encoding the cytosolic catalase T, or CTA1, encoding the mitochondrial matrix catalase, suppresses the peroxide sensitivity in both the sco1 and the cox11 null mutants. Direct measurement of peroxide metabolism shows that sco1 and cox11 null strains fail to degrade a significant amount of exogenously provided H(2)O(2). Taken together, our data demonstrate that although Cox11p and Sco1p play distinct roles in COX assembly, they seem to play overlapping or related roles in peroxide metabolism that require further investigation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Fluctuations in substrate preference and utilization across the circadian cycle may be influenced by the degree of physical activity and nutritional status. In the present study, we assessed these relationships in control mice and in mice from a line selectively bred for high voluntary wheel-running behavior, either when feeding a carbohydrate-rich/low-fat (LF) or a high-fat (HF) diet. Housed without wheels, selected mice, and in particular the females, exhibited higher cage activity than their non-selected controls during the dark phase and at the onset of the light phase, irrespective of diet. This was associated with increases in energy expenditure in both sexes of the selection line. In selected males, carbohydrate oxidation appeared to be increased compared to controls. In contrast, selected females had profound increases in fat oxidation above the levels in control females to cover the increased energy expenditure during the dark phase. This is remarkable in light of the finding that the selected mice, and in particular the females showed higher preference for the LF diet relative to controls. It is likely that hormonal and/or metabolic signals increase carbohydrate preference in the selected females, which may serve optimal maintenance of cellular metabolism in the presence of augmented fat oxidation., ((c) 2010 Elsevier Inc. All rights reserved.)

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., (Copyright 2010 Elsevier B.V. All rights reserved.)

Phox2b is a master regulator of visceral reflex circuits. Its role in the control of respiration has been highlighted by the identification of heterozygous PHOX2B mutations as the cause of Central Congenital Hypoventilation Syndrome (CCHS), a rare disease defined by the lack of CO(2) responsiveness and of breathing automaticity in sleep. Phox2b(27Ala/+) mice that bear a frequent CCHS-causing mutation do not respond to hypercapnia and die in the first hour after birth from central apnoea. They are therefore a reliable animal model for CCHS. Neurons of the retrotrapezoïd nucleus/parafacial respiratory group (RTN/pFRG) were found severely depleted in these mice and no other neuronal loss could be identified. Physiological experiments show that RTN/pFRG neurons are crucial to driving proper breathing at birth and are necessary for central chemoreception and the generation of a normal respiratory rhythm. To date, the reason for the selective vulnerability of RTN/pFRG neurons to PHOX2B protein dysfunction remains unexplained.

A mouse strain with a deleted acetylcholinesterase (AChE) gene (AChE knockout) shows a decreased inspiration time and increased tidal volume and ventilation .To investigate the respective roles of AChE in brain and muscle, we recorded respiration by means of whole-body plethysmography in knockout mice with tissue selective deletions in AChE expression. A mouse strain with the anchoring domains of AChE deleted (del E5+6 knockout mice) has very low activity in the brain and neuromuscular junction, but increased monomeric AChE in serum. A mouse strain with deletion of the muscle specific region of AChE (del i1RR knockout mice) exhibits no expression in muscle, but unaltered expression in the central nervous system. Neither strain exhibits the pronounced phenotypic traits observed in the complete AChE knockout strain. A third strain lacking the anchor molecule PRiMA, has no functional AChE and butyrylcholinesterase (BChE) in brain and an unaltered respiratory function. BChE inhibition by bambuterol decreases tidal volume and body temperature in del E5+6 and i1RR knockout strains, but not in PRiMA deletion or wild-type controls. We find that: (1) deletion of the full AChE gene is required for a pronounced alteration in respiratory phenotype, (2) BChE is involved in respiratory muscles contraction and temperature control in del E5+6 and i1RR knockout mice, and (3) AChE expression requiring a gene product splice to either exons 5 and 6 or regulated by intron1 influences temperature control.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an ancient neuropeptide that predates the evolution of vertebrates. While PACAP acts on multiple target organs and has multiple roles in development, neuronal network function and metabolic homeostasis, it also appears to play an important role in the control of breathing. Mice lacking PACAP die suddenly in the second week of life, a phenotype that is exaggerated by mild thermal stress and bares resemblance to human SIDS. Here we discuss several hypotheses as to why PACAP signaling is important for neonatal survival, focusing on data demonstrating an important role in the control of breathing. We review data suggesting that (a) breathing and respiratory chemosensitivity is blunted in PACAP-deficient mice; (b) PACAP plays an important role in protecting neonatal breathing during thermal stress; and (c) PACAP-signaling occurs in a number of loci important for respiratory control including the carotid bodies (the main peripheral respiratory chemoreceptors) and nuclei in the hypothalamus, pons and medulla, as well as pathways involved in setting sympathetic-parasympathetic tone. Whether PACAP gene abnormalities contribute to Sudden Infant Death Syndrome (SIDS) by reducing respiratory system efficacy during environmental stress remains unanswered.

Gangliosides are a family of sialylated glycosphingolipids enriched in the outer leaflet of neuronal membranes, in particular at synapses. Therefore, they have been hypothesized to play a functional role in synaptic transmission. We have measured in detail the electrophysiological parameters of synaptic transmission at the neuromuscular junction (NMJ) ex vivo of a GD3-synthase knockout mouse, expressing only the O- and a-series gangliosides, as well as of a GM2/GD2-synthase*GD3-synthase double-knockout (dKO) mouse, lacking all gangliosides except GM3. No major synaptic deficits were found in either null-mutant. However, some extra degree of rundown of acetylcholine release at high intensity use was present at the dKO NMJ and a temperature-specific increase in acetylcholine release at 35 degrees C was observed in GD3-synthase knockout NMJs, compared with wild-type. These results indicate that synaptic transmission at the NMJ is not crucially dependent on the particular presence of most ganglioside family members and remains largely intact in the sole presence of GM3 ganglioside. Rather, presynaptic gangliosides appear to play a modulating role in temperature- and use-dependent fine-tuning of transmitter output.

The regulatory effect of substance P on respiration is mediated via neurokinin (NK) receptors. While previous studies suggest that NK-1 receptors are involved, little is known about the role NK-2 receptors in ventilatory responses to hypoxia. Ventilatory responses to acute hypoxia (8% O2 in N2) were measured by indirect plethysmography in unanaesthetized, unrestrained NK-1 receptor gene deficient (NK-1-/-) and wild-type mice. In additional experiments mice were treated with an NK-2 receptor antagonist prior to hypoxic challenge. Resting ventilatory parameters were not different between groups. NK-1-/- mice displayed significantly greater shortening of expiratory time and higher increase of breathing frequency during hypoxia than wild-type mice. Treatment with the NK-2 receptor antagonist SR 48968 (1 mg/kg) resulted in a further shortening of inspiratory and expiratory time in NK-1-/- but not wild-type mice. These results demonstrate that both NK-1 and NK-2 receptors are involved in the modification of ventilation in response to acute hypoxia.

Opioids inhibit breathing in mammals, especially in newborns, and are also implicated in the control of hypoxic anapyrexia. We measured breathing patterns and metabolic responses to 12% oxygen in six adult male wildtype C57B/6J mice and six preproenkephalin knockout (PPNK-/-) mice in a flow-through respirometer and barometric plethysmograph with ambient temperature maintained in the thermoneutral zone. Breathing air, there was no significant difference between the two groups of mice in ventilation ((.)V), oxygen consumption ((.)V(O(2)), convection requirement ((.)V/(.)V(O(2)), tidal volume (V(t)), frequency (f), or inspiratory time (T(i)); however, PPNK-/- mice had a significantly shorter expiratory time (T(e)). The breathing pattern response to 5% CO(2) was the same between wildtype and PPNK-/- in terms of absolute values, but the % change in V(t) was greater in the wildtype. Breathing 12% O(2), there was no significant difference in V , V(t), f, T(i), T(e) or body temperature between groups, but there was a significant difference in (.)V(O(2) (PPNK-/- 1.24+/-0.05 ml O(2)min(-1) versus 0.91+/-0.05 for wildtype, P<0.001) and % change in (.)V(O(2), (2.3+/-6.6% for PPNK-/- versus -28+/-3.8% for wildtype); in ((.)V/(.)V(O(2)), (54+/-4 versus 78+/-10, P<0.05) and the % change in (.)V/(.)V(O(2), (37+/-9 versus 131+/-28, P<0.01). These data implicate enkephalin as a signaling molecule in the control of hypoxic depression of metabolism in mice.

Acetylcholine (ACh) acting through muscarinic receptors is thought to be involved in the control of breathing, notably in central and peripheral chemosensory afferents and in regulations related to sleep-wake states. By using whole-body plethysmography, we compared baseline breathing at rest and ventilatory responses to acute exposure (5 min) to moderate hypoxia (10% O(2)) and hypercapnia (3 and 5% CO(2)) in mice lacking either the M(1) or the M(3) muscarinic receptor, and in wild-type matched controls. M(1) knockout mice showed normal minute ventilation (V(E)) but elevated tidal volume (V(T)) at rest, and normal chemosensory ventilatory responses to hypoxia and hypercapnia. M(3) knockout mice had elevated V(E) and V(T) at rest, a reduced V(T) response slope to hypercapnia, and blunted V(E) and frequency responses to hypoxia. The results suggest that M(1) and M(3) muscarinic receptors play significant roles in the regulation of tidal volume at rest and that the afferent pathway originating from peripheral chemoreceptors involves M(3) receptors.

Genetic factors influence breathing control. Respiratory phenotypes of mutant mice may help to better understand these factors. Congenital central hypoventilation syndrome (CCHS) is a rare disorder defined as failure of chemical control of breathing causing central alveolar hypoventilation, especially during sleep. A genetic basis for CCHS is supported by several arguments, mainly the identification, in a few CCHS patients, of heterozygous mutations of genes contributing to neural crest cell development, namely, genes involved in the endothelin and c-ret pathways. Furthermore, plethysmography studies of the respiratory phenotypes of newborn heterozygous mutant mice have shown that genes in both pathways are involved in breathing control at birth. Nevertheless, no single gene mutation in newborn mice reproduces the human CCHS phenotype. Avenues for future research into the genetics of CCHS include (i) testing of mutant newborn mice for genes in other pathways and (ii) use of microarrays to identify gene clusters that should be associated with abnormal chemical breathing control.

Neurotrophic molecules, released by neurons and neural target tissues, play a pivotal role in regulating neuronal development and plasticity. This article reviews recent work demonstrating the pivotal role of two such molecules, brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), in the growth and maturation of respiratory neurons and the expression of normal ventilatory behavior. Although BDNF and GDNF are structurally dissimilar and signal through wholly distinct receptors, they are both required for development of peripheral chemoafferent neurons that provide hypoxic drive to the brainstem respiratory network. Studies of genetically engineered mice carrying targeted deletions in the genes encoding BDNF and GDNF, as well as genetic linkage analysis in humans, indicate that these trophic molecules may be candidate genes for human developmental disorders of breathing.

Functional genomics is a systematic and high-throughput effort to analyze the functions of genes and gene products. Functional genomics is divided into gene- and phenotype-driven approaches. Gene-driven approaches to the functional genomics of sleep have demonstrated that transcripts of many genes change as a function of behavioral state. A phenotype-driven approach includes identification and characterization of gene function through the analyses of natural polygenic traits, creation of transgenic animals or high-throughput mutagenesis. Identification of a gene for narcolepsy through QTL analyses and concomitantly using a transgenic approach is one example of the phenotype-driven approach to the functional genomics of sleep. Though the majority of functional genomics is currently performed in mice, the rat is emerging as an important model for genomic research. Since rest in Drosophila shares many features with mammalian sleep, this allows a comparative functional genomics approach to the study of rest and sleep. The concepts outlined here for the functional genomics of sleep are applicable to respiration research.

Indeed, specific genes in humans and mice regulate breathing pattern at baseline and breathing control during chemical stimulation. The current review addresses the question of coupling plausible candidate genes to physiological variation in control of breathing. That is, can genes discovered in mice be candidates assigned to similar physiological mechanisms as genetic control of breathing in humans? As an illustration, this review examines the interaction of hypoxia in affecting the hypercapnic ventilatory sensitivity (HCVS) curve in humans and mice. Strain distribution patterns (SDPs) incorporating ten inbred mouse strains demonstrate that hypoxic stimulation likely influences HVCS via an additive mechanism rather than synergy between hypercapnia and hypoxia (i.e. CO(2) potentiation). As a mechanism associated with the chemical control of breathing in humans, the absence of CO(2) potentiation in mice suggests that specific genes interact to establish variation in complex breathing traits among mouse strains and between species. If future studies support the current evidence, the absence of CO(2) potentiation in mice compared with humans suggest a clearly defined species difference, which may depend on alternative hypoxic interactions such as hypometabolic and central neuronal depressive mechanisms in mice. Because the complexity of breathing mechanisms varies with modest adjustments in the environment, gene-targeting strategies that achieve 'one-gene, one-phenotype' results must be complimented with alternative strategies that consider integrating complex respiratory mechanisms with gene-to-gene interactions.

This article highlights major findings from physiological and pharmacological studies conducted in the pre- and post-genomic era examining the roles of substance P (SP) and other tachykinins in the response of the carotid body to hypoxia, in the ventilatory response to hypoxia and in respiratory rhythm generation. In the post-genomic period, the hypoxic ventilatory responses of mice carrying targeted deletion of genes that affect synthesis or degradation or receptor interaction of SP have been examined by us and also by other investigators. A brief summary of the findings from these investigations will also be presented. The combined observations from the pre- and post-genomic era strongly support the involvement of SP and also other tachykinins in the control of respiration during hypoxia.

The present paper presents some of the molecular switches that may operate at early embryonic stages to make development of the brainstem respiratory rhythm generator a robust and irreversible process. We concentrate on the role of transient Hox-related gene expression patterns in register with the regionalisation of the rhombencephalic neural tube along the antero-posterior axis. Using different recording and isolation procedures in chick embryos, we show that the hindbrain is subdivided at E1 into developmental units (rhombomeres) intrinsically able to produce rhythm generating neuronal circuits active at E5. At E6, intrinsic cues also allow a progressive maturation of episodic rhythm generators that persists after isolation of the hindbrain in vitro and requires odd/even rhombomeric interactions at E1. From these results and from respiratory pathologies observed in transgenic mice, we are beginning to understand that, despite diversity of breathing patterns and adaptations, there are links between developmental control genes and adult respiration.

New genomic and proteomic techniques offer remarkable promise as tools to address longstanding questions regarding molecular mechanisms involved in the control of breathing. Here, these techniques are described. Additionally, recent examples of the application of these and related molecular techniques are provided-particularly including observations regarding the role of S-nitrosylation signaling reactions in regulating ventilatory responses.

As part of a large scale, high through-put physiologic genomics study, we sought to determine whether genes on rat chromosomes 9, 13, 16, 18, and 20 contribute to phenotypic differences in the control of breathing between two inbred rat strains (SS/Mcw and BN/Mcw). Through a chromosomal substitution breeding strategy, we created 5 consomic rat strains (SS.BN9, SS.BN13, SS.BN16, SS.BN18, and SS.BN20), which were BN/Mcw homozygous at only one chromosome and SS/Mcw homozygous at all other chromosomes. Standard plethsmography was used to assess eupneic breathing and ventilatory responses to CO(2) (FI(CO(2))=0.07) and hypoxia (FI(CO(2))=0.12), and Pa(CO(2)) during treadmill exercises provided the index of the exercise hyperpnea. There were no robust differences in eupneic breathing between any strains. The ventilatory response to CO(2) was 150% greater (P<0.001) in the SS/Mcw rats than in the BN/Mcw rats and all consomic strains had the SS/Mcw phenotype. Hyperventilation during hypoxia did not differ between the parental and the consomic strains, but ventilation during hypoxia was greater (P<0.001) in the SS/Mcw than in the BN/Mcw, and the SS.BN9, and SS.BN18 appeared to acquire this BN/Mcw phenotype. The hyperventilation during treadmill walking was greater (P<0.006) in the BN/Mcw and the SS.BN18 rats than in the SS/Mcw rats. Finally, the duration of the apnea following an augmented breath (post sigh apnea, PSA) was greater (P<0.001) in the BN/Mcw and the SS.BN9 rats than all other strains. We conclude that the robust difference between the parental strains in ventilatory CO(2) sensitivity is not due to genotypic differences on the 5 chromosomes studied to date, but genotypic differences on chromosomes 9 and 18 contribute to differences in ventilatory responses to hypoxia, exercise, and/or to the differences in the PSA.

The episodic waxing and waning of ventilation is a fundamental event in sleep apnea syndromes. Post-hypoxic frequency decline (PHFD) and periodic breathing (PB) are evoked by brief hypoxic exposures in unanaesthetized and unrestrained inbred C57BL/6J mice, but not in A/J mice; and expression of PHFD differs not only among these mice strains but in among rat strains as well. These observations along with the current literature on genetic factors that operate on ventilatory behavior at rest and with chemosensory drive lead to the hypothesis that genetic factors infer some proportion of risk for the ventilatory instability observed in human sleep apnea syndromes.

We examined the respiratory response to moderate hypercapnia in rat pups during the first 10 days after birth and also studied immediate early gene expression to investigate whether areas described as chemosensitive in the adult rat are activated also in the early postnatal period. Breathing frequency increased in 1- and 3-day-old pups, but decreased in older animals in response to hypercapnia. Tidal volume and ventilation increased significantly in all age groups but relatively more in the 10-day-old pups as compared to younger animals. In situ hybridisation for c-fos mRNA revealed increased expression in several of the areas assigned as chemosensitive in the adult, including the caudal nucleus tractus solitarii and the ventral lateral medulla. In contrast, locus coeruleus and the majority of midline raphe neurons did not exhibit increased expression of c-fos mRNA. We conclude that the hypercapnic respiratory response tends to decrease during the first postnatal week, but thereafter increases on day 10 due to increased tidal volumes rather than changes in respiratory timing. We also speculate that differences in activation of chemosensitive brainstem neurons may be part of the maturation of the hypercapnic ventilatory response.

The effects of a deficiency of glycinergic inhibition deriving from mutations of the glycine-receptor gene Glra1 on the breathing pattern of oscillator mice were studied. We compared the development of breathing frequency, tidal volume and minute ventilation from control mice (wild type- and heterozygous oscillator mice) with those of homozygous oscillator mice during early postnatal periods from p9 until p21. The changes of ventilation were correlated with body-weight and changes in blood-pH. During the second to third weeks of postnatal development, breathing frequency increased from 310 to 445.4 mm-1 in control mice. Oscillator mice reached a maximal value of 313.3 min-1 at p18 followed by a fast decrease to 233.0 min-1. This decrease is caused by a prolongation of expiratory duration. Tidal volume showed a steady increase from 6.6 to 15.1 microliters in control animals. In comparison, oscillator mice showed significant lower values after p14. After p15, minute ventilation of oscillator mice declined as compared with control animals leading to respiratory acidosis at p20.