Brain‐derived neurotrophic factor is required for normal development of the central respiratory rhythm in mice

Bałkowiec, Agnieszka; Katz, David M.

doi:10.1111/j.1469-7793.1998.527bk.x

Cited by 84 publications

(57 citation statements)

References 29 publications

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“…This suggestion provides a rationale for the use of methylxanthines to reduce the number of neonatal apneas. In an in vitro brainstem spinal cord preparation from A 1 R ϩ/ϩ mice (15,16), hypoxia induced a transient (1-2 min) increase in C4 ϩ/Ϫ and A1R ϩ/ϩ mice (ANOVA F(2,41) ϭ 3.765, P Ͻ 0.05; versus both A1R ϩ/Ϫ and A1R ϩ/ϩ , Duncan's multiple range test; after sqrt transformation for reducing heterogeneity of variances). (Bottom) The number of entries into the lit compartment (mean Ϯ SEM) was also reduced in A 1R Ϫ/Ϫ compared with both A 1R ϩ/Ϫ and A1R ϩ/ϩ mice (ANOVA F(2,41) ϭ 3.654, P Ͻ 0.05; Duncan's multiple range test).…”

Section: Resultsmentioning

confidence: 99%

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Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A₁receptor

Johansson

Halldner²,

Dunwiddie³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

469

396

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Caffeine is believed to act by blocking adenosine A1 and A2A receptors (A1R, A2AR), indicating that some A1 receptors are tonically activated. We generated mice with a targeted disruption of the second coding exon of the A1R (A1R ؊/؊ ). These animals bred and gained weight normally and had a normal heart rate, blood pressure, and body temperature. In most behavioral tests they were similar to A1R ؉/؉ mice, but A1R ؊/؊ mice showed signs of increased anxiety. Electrophysiological recordings from hippocampal slices revealed that both adenosine-mediated inhibition and theophylline-mediated augmentation of excitatory glutamatergic neurotransmission were abolished in A1R ؊/؊ mice. In A1R ؉/؊ mice the potency of adenosine was halved, as was the number of A1R. In A 1R؊/؊ mice, the analgesic effect of intrathecal adenosine was lost, and thermal hyperalgesia was observed, but the analgesic effect of morphine was intact. The decrease in neuronal activity upon hypoxia was reduced both in hippocampal slices and in brainstem, and functional recovery after hypoxia was attenuated. Thus A1Rs do not play an essential role during development, and although they significantly influence synaptic activity, they play a nonessential role in normal physiology. However, under pathophysiological conditions, including noxious stimulation and oxygen deficiency, they are important. A denosine acts on four cloned and pharmacologically characterized receptors, A 1 , A 2A , A 2B , and A 3 (1). Adenosine is believed to play a particularly important role in hypoxia and ischemia, and there is evidence that adenosine serves to limit damage secondary to ATP loss (2, 3). However, adenosine may have important actions under more normal physiological circumstances as well. For instance, the effects of caffeine, at concentrations reached during habitual caffeine consumption, are believed to be a consequence of blockade of tonic activity at some A 1 and A 2A receptors (A 1 R and A 2A R) (4). Studies on mice lacking A 2A Rs show that adenosine tonically activates A 2A Rs and that this activation has functional effects, particularly on behavior, blood pressure, and blood platelets (5). A 1 Rs are more widely distributed than A 2A Rs (4, 6), but despite extensive pharmacological studies their physiological and pathophysiological roles remain unclear. Here we show that A 1 Rs mediate physiological as well as pathophysiological effects of endogenous adenosine. In particular, adenosine acts tonically to activate presynaptic and postsynaptic A 1 Rs to depress synaptic transmission and to reduce nociceptive signaling. At elevated levels seen during hypoxia, adenosine acting at A 1 Rs is responsible for the depression of neuronal activity, and in this situation elimination of A 1 Rs results in impaired functional recovery. Materials and MethodsGeneration of A1R Knockout Mice. A major part of the proteincoding sequence of the mouse A 1 R gene (7) corresponding to exon 6 of the human A 1 R gene described by Ren and Stiles (8) was cloned. The targeting construct was b...

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Section: Resultsmentioning

confidence: 99%

“…Brainstem-spinal cord preparations were isolated under ether anesthesia from P1-P4 mice (46 preparations) as described in detail elsewhere (15,16). Briefly, the brainstem was rostrally decerebrated between VIth cranial nerve roots and the lower border of the trapezoid body so that the pons was removed.…”

Section: Analgesiamentioning

confidence: 99%

Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A₁receptor

Johansson

Halldner²,

Dunwiddie³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

469

396

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“…Development of the respiratory rhythm is severely disrupted in newborn mice carrying a targeted deletion in the gene encoding brain-derived neurotrophic factor (BDNF) (Erickson et al, 1996;Balkowiec and Katz, 1998), a member of the neurotrophin family of growth factors. In particular, central respiratory output and ventilation are depressed and irregular in BDNF null mutants, and the animals die shortly after birth.…”

Section: Introductionmentioning

confidence: 99%

Expression of Functional Tyrosine Kinase B Receptors by Rhythmically Active Respiratory Neurons in the Pre-Bötzinger Complex of Neonatal Mice

et al. 2003

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Genetic loss of brain-derived neurotrophic factor (BDNF) severely disrupts brainstem control of respiratory rhythmogenesis in newborn mice; however, the sites at which BDNF acts to regulate respiratory rhythmogenesis are unknown. Using immunochemical and multiplex RT-PCR analysis in mouse brainstem slices, we report that the BDNF receptor, Tyrosine kinase B (TrkB), is strongly expressed in the pre-Bötzinger complex (PBC), the presumed site for rhythm generation, and colocalizes with neurokinin 1 (NK1), a marker of neurons critical for breathing. The period of the respiratory rhythm generated by PBC neurons in vitro was increased by 30% after BDNF treatment (100 ng/ml) and not by nerve growth factor (100 ng/ml) or BDNF (100 ng/ml) in the presence of the tyrosine kinase inhibitor K252a (200 nM). Both synaptic and voltage-dependent properties of PBC neurons were modified by BDNF. Synaptic currents underlying spontaneous rhythmic bursts and glutamate-evoked currents were enhanced by 66 and 33%, respectively. BDNF reduced the I h current amplitude in rhythmic neurons by 46% and shifted its activation curve by Ϫ17 mV. All neurons expressing TrkB mRNA (n ϭ 8) also expressed mRNAs for the I h current [hyperpolarization-activated cyclic nucleotide-sensitive cation nonselective channel (HCN1)], and three of four NK1-positive neurons coexpressed TrkB and HCN mRNA. Six of 16 PBC neurons expressed BDNF mRNA, supporting the possibility of autocrine and paracrine actions of BDNF within the respiratory pattern generator. Our data demonstrate that BDNF can modulate respiratory network activity through TrkB signaling in rhythmic PBC neurons.

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“…Baseline respiratory frequency was decreased in both GDNFϪ/Ϫ and BDNFϪ/Ϫ newborn mice (43,44). Recordings of brainstemspinal cord preparations from BDNF mutant mice showed discharge frequency attenuation, which was more marked in homozygous than in heterozygous newborns (45). MASH1Ϫ/Ϫ and MASH1ϩ/Ϫ newborns had an abnormally fast respiratory rate (42), a finding that has never been reported in CCHS patients.…”

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confidence: 82%

Genetics and Early Disturbances of Breathing Control: The Genetics of Childhood Disease and Development: A Series of Review Articles

et al. 2004

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Médicale, 75743 Paris, France [J.A., S.L.] Early disturbances in breathing control, including apneas of prematurity and apparently life-threatening events, account for some cases of sudden infant death syndrome and for a rare disorder called congenital central hypoventilation syndrome (CCHS). Data suggesting a genetic basis for CCHS have been obtained. Recently, we found heterozygous de novo mutations of the PHOX2B gene in 18 of 29 individuals with CCHS. Most mutations consisted of five to nine alanine expansions within a 20-residue polyalanine tract, probably resulting from nonhomologous recombination. Other mutations, generally inherited from one of the parents, in the coding regions of genes involved in the endothelin and RET signaling pathways and in the brain-derived-neurotrophic factor (BDNF) gene have been found in a few CCHS patients. Interestingly, all these genes are involved in the development of neural crest cells. Targeted disruption of these genes in mice has provided information on the pathophysiological mechanisms underlying CCHS. Despite the identification of these genes involved in breathing control, none of the genetically engineered mice developed to date replicate the full human CCHS respiratory phenotype. Recent insights into the genetic basis for CCHS may shed light on the genetics of other early disturbances in breathing control, such as apnea of prematurity and sudden infant death syndrome.

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Brain‐derived neurotrophic factor is required for normal development of the central respiratory rhythm in mice

Cited by 84 publications

References 29 publications

Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A₁receptor

Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A₁receptor

Expression of Functional Tyrosine Kinase B Receptors by Rhythmically Active Respiratory Neurons in the Pre-Bötzinger Complex of Neonatal Mice

Genetics and Early Disturbances of Breathing Control: The Genetics of Childhood Disease and Development: A Series of Review Articles

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Brain‐derived neurotrophic factor is required for normal development of the central respiratory rhythm in mice

Cited by 84 publications

References 29 publications

Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1receptor

Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1receptor

Expression of Functional Tyrosine Kinase B Receptors by Rhythmically Active Respiratory Neurons in the Pre-Bötzinger Complex of Neonatal Mice

Genetics and Early Disturbances of Breathing Control: The Genetics of Childhood Disease and Development: A Series of Review Articles

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Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A₁receptor

Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A₁receptor