BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia

Baker-Herman, Tracy L.; Fuller, David D.; Bavis, Ryan W.; Zabka, A. G.; Golder, Francis J.; Doperalski, Nicholas J.; Johnson, Rebecca A.; Watters, Jyoti J.; Mitchell, Gordon S.

doi:10.1038/nn1166

Cited by 437 publications

(448 citation statements)

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“…pLTF is initiated by serotonin receptor activation on or near phrenic motoneurons after intermittent, but not sustained, exposure to hypoxia (Baker and Mitchell, 2000;Baker-Herman et al, 2004;McKay et al, 2004). Intermittent (but not sustained) serotonin receptor activation is sufficient to induce pLTF in in vitro neonatal rat brainstem-spinal cord preparations (Lovett-Barr et al, 2006) and in anesthetized adult rats (P. M. MacFarlane and G. S. Mitchell, unpublished observations), similar to serotonin-induced hypoglossal LTF in in vitro neonatal brainstem slice preparations (Bocchiaro and Feldman, 2004).…”

Section: Introductionmentioning

confidence: 79%

“…Simultaneously, serotonergic raphe neurons are activated, releasing serotonin near phrenic motor neurons and activating postsynaptic 5-HT 2 receptors , thereby leading to activation of protein kinases, such as protein kinase C (McGuire and Ling, 2004). We postulate that protein kinase activation initiates new protein synthesis, including synthesis of brain-derived neurotrophic factor (BDNF); subsequent BDNF release would activate its high-affinity receptor tyrosine kinase, TrkB (Baker-Herman et al, 2004). TrkB receptor activation in turn activates protein kinases, such as extracellular regulated kinases 1 and 2 (ERK 1/2) and protein kinase B (Akt) that are postulated to regulate glutamatergic receptor density at the postsynaptic membrane and, thus, motor neuron responses to descending respiratory drive (Huang and Reichardt, 2003).…”

Section: Working Model Of Phrenic Ltf and Pattern Sensitivitymentioning

confidence: 99%

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Okadaic Acid-Sensitive Protein Phosphatases Constrain Phrenic Long-Term Facilitation after Sustained Hypoxia

Wilkerson¹,

Satriotomo²,

Baker-Herman³

et al. 2008

J. Neurosci.

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Phrenic long-term facilitation (pLTF) is a serotonin-dependent form of pattern-sensitive respiratory plasticity induced by intermittent hypoxia (IH), but not sustained hypoxia (SH). The mechanism(s) underlying pLTF pattern sensitivity are unknown. SH and IH may differentially regulate serine/threonine protein phosphatase activity, thereby inhibiting relevant protein phosphatases uniquely during IH and conferring pattern sensitivity to pLTF. We hypothesized that spinal protein phosphatase inhibition would relieve this braking action of protein phosphatases, thereby revealing pLTF after SH. Anesthetized rats received intrathecal (C4) okadaic acid (25 nM) before SH (25 min, 11% O 2 ). Unlike (vehicle) control rats, SH induced a significant pLTF in okadaic acid-treated rats that was indistinguishable from rats exposed to IH (three 5 min episodes, 11% O 2 ). IH and SH with okadaic acid may elicit pLTF by similar, serotonin-dependent mechanisms, because intravenous methysergide blocks pLTF in rats receiving IH or okadaic acid plus SH. Okadaic acid did not alter IH-induced pLTF. In summary, pattern sensitivity in pLTF may reflect differential regulation of okadaic acid-sensitive serine/threonine phosphatases; presumably, these phosphatases are less active during/after IH versus SH. The specific okadaic acid-sensitive phosphatase(s) constraining pLTF and their spatiotemporal dynamics during and/or after IH and SH remain to be determined.

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Section: Introductionmentioning

confidence: 79%

Section: Working Model Of Phrenic Ltf and Pattern Sensitivitymentioning

confidence: 99%

Okadaic Acid-Sensitive Protein Phosphatases Constrain Phrenic Long-Term Facilitation after Sustained Hypoxia

Wilkerson¹,

Satriotomo²,

Baker-Herman³

et al. 2008

J. Neurosci.

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“…An important body of literature shows that LTF depends on activation of brain stem raphe neurons, leading to spinal serotonin release and serotonin receptor activation (15), which leads to de novo brain-derived neurotrophic factor synthesis, strengthening synaptic efficiency on spinal respiratory motoneurons (2,34). Other mechanisms involve spinal adenosine, and adenosine A 2A receptors, which enhances phrenic activity in the absence of hypoxia (16) but reduces the magnitude of LTF induced by IH (22).…”

Section: Respiratory Responses To Repeated Hypoxic Cycles In Control mentioning

confidence: 99%

Carotid sinus nerve stimulation, but not intermittent hypoxia, induces respiratory LTF in adult rats exposed to neonatal intermittent hypoxia

Julien

Niane

Kinkead

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Julien CA, Niane L, Kinkead R, Bairam A, Joseph V. Carotid sinus nerve stimulation, but not intermittent hypoxia, induces respiratory LTF in adult rats exposed to neonatal intermittent hypoxia. Am J Physiol Regul Integr Comp Physiol 299: R192-R205, 2010. First published April 21, 2010 doi:10.1152/ajpregu.00707.2009.-We tested the hypothesis that exposure to neonatal intermittent hypoxia (n-IH) in rat pups alters central integrative processes following acute and intermittent peripheral chemoreceptor activation in adults. Newborn male rats were exposed to n-IH or normoxia for 10 consecutive days after birth. We then used both awake and anesthetized 3-to 4-mo-old rats to record ventilation, blood pressure, and phrenic and splanchnic nerve activities to assess responses to peripheral chemoreflex activation (acute hypoxic response) and long-term facilitation (LTF, long-term response after intermittent hypoxia). In anesthetized rats, phrenic and splanchnic nerve activities and hypoxic responses were also recorded with or without intact carotid body afferent signal (bilateral chemodenervation) or in response to electrical stimulations of the carotid sinus nerve. In awake rats, n-IH alters the respiratory pattern (higher frequency and lower tidal volume) and increased arterial blood pressure in normoxia, but the ventilatory response to repeated hypoxic cycles was not altered. In anesthetized rats, phrenic nerve responses to repeated hypoxic cycles or carotid sinus nerve stimulation were not altered by n-IH; however, the splanchnic nerve response was suppressed by n-IH compared with control. In control rats, respiratory LTF was apparent in anesthetized but not in awake animals. In n-IH rats, respiratory LTF was not apparent in awake and anesthetized animals. Following intermittent electrical stimulation, however, phrenic LTF was clearly present in n-IH rats, being similar in magnitude to controls. We conclude that, in adult n-IH rats: 1) arterial blood pressure is elevated, 2) peripheral chemoreceptor responses to hypoxia and its central integration are not altered, but splanchnic nerve response is suppressed, 3) LTF is suppressed, and 4) the mechanisms involved in the generation of LTF are still present but are masked most probably as the result of an augmented inhibitory response to hypoxia in the central nervous system. neonatal intermittent hypoxia; long-term facilitation DEVELOPMENT OF THE RESPIRATORY control system is tightly regulated by complex interactions between genetic and environmental factors that contribute to shape the mature phenotypic expression of this neural network (4). Over the past years, several studies have documented that alterations in environmental oxygen levels during development lead to important changes of the respiratory control system (4). A particular importance has been given to intermittent hypoxic exposure (38, 47, 50) because it may be used in laboratory animals to reproduce some of the effects encountered in human newborn suffering from apneas, which remains one of the major cause...

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“…5-HT neurons respond to hypercapnic acidosis with an increase in activity in vitro (Richerson, 1995;Wang et al, 2001), and in vivo (Larnicol et al, 1994;Veasey et al, 1995;Haxhiu et al, 2001;Johnson et al, 2005), and this causes an increase in 5-HT release in vivo (Kanamaru and Homma, 2007), indicating that 5-HT neurons are modulated by the acid/base status of the brain. There is also evidence for a trophic role for 5-HT, especially during development and after CNS injury (Golder and Mitchell, 2005), as well as a permissive effect for some forms of plasticity such as long-term facilitation of respiratory motor output (Baker-Herman et al, 2004). Thus, the mechanisms of action, specific role, and relative importance of 5-HT and/or 5-HT neurons in respiratory control are complex and remain unclear (Richerson, 2004;Guyenet et al, 2005;Richerson et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Defects in Breathing and Thermoregulation in Mice with Near-Complete Absence of Central Serotonin Neurons

Hodges¹,

Tattersall²,

Harris³

et al. 2008

J. Neurosci.

294

348

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f/f/p mice was decreased by 50% compared with wild-type mice, whereas baseline ventilation and the hypoxic ventilatory response were normal. In addition, Lmx1b f/f/p mice rapidly became hypothermic when exposed to an ambient temperature of 4°C, decreasing core temperature to 30°C within 120 min. This failure of thermoregulation was caused by impaired shivering and nonshivering thermogenesis, whereas thermosensory perception and heat conservation were normal. Finally, intracerebroventricular infusion of 5-HT stimulated baseline ventilation, and rescued the blunted hypercapnic ventilatory response. These data identify a previously unrecognized role of 5-HT neurons in the CO 2 chemoreflex, whereby they enhance the response of the rest of the respiratory network to CO 2 . We conclude that the proper function of the 5-HT system is particularly important under conditions of environmental stress and contributes significantly to the hypercapnic ventilatory response and thermoregulatory cold defense.

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BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia

Cited by 437 publications

References 50 publications

Okadaic Acid-Sensitive Protein Phosphatases Constrain Phrenic Long-Term Facilitation after Sustained Hypoxia

Okadaic Acid-Sensitive Protein Phosphatases Constrain Phrenic Long-Term Facilitation after Sustained Hypoxia

Carotid sinus nerve stimulation, but not intermittent hypoxia, induces respiratory LTF in adult rats exposed to neonatal intermittent hypoxia

Defects in Breathing and Thermoregulation in Mice with Near-Complete Absence of Central Serotonin Neurons

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