Ventilatory effects of gap junction blockade in the RTN in awake rats

Hewitt, Amy; Barrie, Rachel; Graham, Michael R.; Bogus, Kara; Leiter, James C.; Erlichman, Joseph S.

doi:10.1152/ajpregu.00404.2004

Cited by 18 publications

(14 citation statements)

References 72 publications

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“…Frequent gap junctions contribute to the synchronous firing of raphe neurons [45] and may lead the brainstem chemoreceptors to behave as a syncytium [47]. Blockade of gap junctions reduces the in vivo RTN/pFRG chemosensitivity [48] and the in vitro resting PBf [49]. Interestingly, the gap junction coupling is reduced by excess of 5-HT [50], [51].…”

Section: Discussionmentioning

confidence: 99%

Fluoxetine Treatment Abolishes the In Vitro Respiratory Response to Acidosis in Neonatal Mice

Voituron

Shvarev²,

Menuet³

et al. 2010

PLoS ONE

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BackgroundTo secure pH homeostasis, the central respiratory network must permanently adapt its rhythmic motor drive to environment and behaviour. In neonates, it is commonly admitted that the retrotrapezoid/parafacial respiratory group of neurons of the ventral medulla plays the primary role in the respiratory response to acidosis, although the serotonergic system may also contribute to this response.Methodology/Principal FindingsUsing en bloc medullary preparations from neonatal mice, we have shown for the first time that the respiratory response to acidosis is abolished after pre-treatment with the serotonin-transporter blocker fluoxetine (25–50 µM, 20 min), a commonly used antidepressant. Using mRNA in situ hybridization and immunohistology, we have also shown the expression of the serotonin transporter mRNA and serotonin-containing neurons in the vicinity of the RTN/pFRG of neonatal mice.ConclusionsThese results reveal that the serotonergic system plays a pivotal role in pH homeostasis. Although obtained in vitro in neonatal mice, they suggest that drugs targeting the serotonergic system should be used with caution in infants, pregnant women and breastfeeding mothers.

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Section: Discussionmentioning

confidence: 99%

Fluoxetine Treatment Abolishes the In Vitro Respiratory Response to Acidosis in Neonatal Mice

Voituron

Shvarev²,

Menuet³

et al. 2010

PLoS ONE

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“…Each cannula made a small hole in the tissue at the end of the cannula track, and the placement of the cannula was determined by identifying the section with the largest lucent cross-sectional area. The tissue stained by Fast Green was located directly adjacent to the tip of the guide cannula (ϳ600 m in diameter), as in our previous studies in the RTN (Holleran et al, 2001;Hewitt et al, 2004;Parisian et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Monocarboxylate Transporter 2 in the Retrotrapezoid Nucleus in Rats: A Test of the Astrocyte–Neuron Lactate-Shuttle Hypothesis

Erlichman¹,

Hewitt²,

Damon³

et al. 2008

J. Neurosci.

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The astrocyte-neuronal lactate-shuttle hypothesis posits that lactate released from astrocytes into the extracellular space is metabolized by neurons. The lactate released should alter extracellular pH (pHe), and changes in pH in central chemosensory regions of the brainstem stimulate ventilation. Therefore, we assessed the impact of disrupting the lactate shuttle by administering 100 M ␣-cyano-4-hydroxycinnamate (4-CIN), a dose that blocks the neuronal monocarboxylate transporter (MCT) 2 but not the astrocytic MCTs (MCT1 and MCT4). Administration of 4-CIN focally in the retrotrapezoid nucleus (RTN), a medullary central chemosensory nucleus, increased ventilation and decreased pHe in intact animals. In medullary brain slices, 4-CIN reduced astrocytic intracellular pH (pHi) slightly but alkalinized neuronal pHi. Nonetheless, pHi fell significantly in both cell types when they were treated with exogenous lactate, although 100 M 4-CIN significantly reduced the magnitude of the acidosis in neurons but not astrocytes. Finally, 4-CIN treatment increased the uptake of a fluorescent 2-deoxy-D-glucose analog in neurons but did not alter the uptake rate of this 2-deoxy-D-glucose analog in astrocytes. These data confirm the existence of an astrocyte to neuron lactate shuttle in intact animals in the RTN, and lactate derived from astrocytes forms part of the central chemosensory stimulus for ventilation in this nucleus. When the lactate shuttle was disrupted by treatment with 4-CIN, neurons increased the uptake of glucose. Therefore, neurons seem to metabolize a combination of glucose and lactate (and other substances such as pyruvate) depending, in part, on the availability of each of these particular substrates.

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“…Gap junctions may play a role in the regulation of ventilation during development before the maturation of synaptic connections (11, 44, 58 -60, 62). Gap junctions have been shown to enhance or amplify the CO 2 response observed in younger animals in the RTN and NTS (30). In a recent study, Hartzler et al (28) provided evidence that gap junctions influence the percentage of LC neurons with intrinsic chemosensitivity at different ages during development from P0 up to P18.…”

Section: Comparison To Previous Work On Chemosensitivity Of Lc Neuronsmentioning

confidence: 99%

GFP-expressing locus ceruleus neurons from Prp57 transgenic mice exhibit CO₂/H⁺ responses in primary cell culture

Johnson

Haxhiu

Richerson

2008

Journal of Applied Physiology

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Johnson SM, Haxhiu MA, Richerson GB. GFP-expressing locus ceruleus neurons from Prp57 transgenic mice exhibit CO 2/H ϩ responses in primary cell culture. J Appl Physiol 105: 1301-1311. First published July 17, 2008 doi:10.1152/japplphysiol.90414.2008.-The locus ceruleus (LC) contains neurons that increase their firing rate (FR) in vitro when exposed to elevated CO2/H ϩ and have been proposed to influence the respiratory network to make compensatory adjustments in ventilation. Prp57 transgenic mice express green fluorescent protein (GFP) in the LC and were used to isolate, culture, and target LC neurons for electrophysiological recording. We hypothesized that GFP-LC neurons would exhibit CO2/H ϩ chemosensitivity under primary culture conditions, evidenced as a change in FR. This is the first study to quantify CO2/H ϩ responses in LC neuron FR in cell culture. Neurons were continuously bathed with solutions containing antagonists of glutamate and GABA receptors, and the acidbase status was changed from control (5% CO2; pH ϳ7.4) to hypercapnic acidosis (9% CO 2; pH ϳ7.2) and hypocapnic alkalosis (3% CO 2; pH ϳ7.6). FR was quantified during perforated patch current clamp recordings. Approximately 86% of GFP-LC neurons were stimulated, and ϳ14% were insensitive to changes in CO2/H ϩ . The magnitude of the response of these neurons depended on the baseline FR, ranging from 155.9 Ϯ 6% when FR started at 2.95 Ϯ 0.49 Hz to 381 Ϯ 55.6% when FR started at 1.32 Ϯ 0.31 Hz. These results demonstrate that cultured LC neurons from Prp57 transgenic mice retain functional sensing molecules necessary for CO 2/H ϩ responses. Prp57 transgenic mice will serve as a valuable model to delineate mechanisms involved in CO2/H ϩ responsiveness in catecholaminergic neurons.CO2/H ϩ chemosensitivity; central respiratory chemoreceptors; carbon dioxide; primary cell culture; pH response CENTRAL RESPIRATORY CHEMORECEPTORS detect fluctuations in CO 2 and/or pH, alter their neuronal activity, and subsequently influence the respiratory network to appropriately adjust ventilation. Chemoreceptors were first proposed to be located in distinct cellular aggregations at or near the ventrolateral medullary surface (37, 57). However, it is now well established that there are many neurons widely distributed along the neuraxis that increase their firing rate (FR) in response to acidosis, including cells within the ventrolateral medullary surface (36,37,57), medullary raphé (6,49,51,70,71,74), pre-Bötzinger complex (34,52,61), retrotrapezoid nucleus (RTN) (20, 27, 56), hypothalamus (15, 16, 75), nucleus tractus solitarius (NTS), and locus ceruleus (LC) (12,18,22,23,28,33,40,42,53,55). It has been proposed that all of these groups of pH-sensitive neurons are central respiratory chemoreceptors, each one contributing to the increased respiratory motor output to ensure that the pH of the blood and cerebrospinal fluid is restricted to normal physiological limits (9, 10, 41). The relative importance of each one to the overall response, and the conditions under whi...

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Ventilatory effects of gap junction blockade in the RTN in awake rats

Cited by 18 publications

References 72 publications

Fluoxetine Treatment Abolishes the In Vitro Respiratory Response to Acidosis in Neonatal Mice

Fluoxetine Treatment Abolishes the In Vitro Respiratory Response to Acidosis in Neonatal Mice

Inhibition of Monocarboxylate Transporter 2 in the Retrotrapezoid Nucleus in Rats: A Test of the Astrocyte–Neuron Lactate-Shuttle Hypothesis

GFP-expressing locus ceruleus neurons from Prp57 transgenic mice exhibit CO₂/H⁺ responses in primary cell culture

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Ventilatory effects of gap junction blockade in the RTN in awake rats

Cited by 18 publications

References 72 publications

Fluoxetine Treatment Abolishes the In Vitro Respiratory Response to Acidosis in Neonatal Mice

Fluoxetine Treatment Abolishes the In Vitro Respiratory Response to Acidosis in Neonatal Mice

Inhibition of Monocarboxylate Transporter 2 in the Retrotrapezoid Nucleus in Rats: A Test of the Astrocyte–Neuron Lactate-Shuttle Hypothesis

GFP-expressing locus ceruleus neurons from Prp57 transgenic mice exhibit CO2/H+ responses in primary cell culture

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GFP-expressing locus ceruleus neurons from Prp57 transgenic mice exhibit CO₂/H⁺ responses in primary cell culture