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

Parisian, Keely; Wages, Page; Smith, Amber; Jarosz, John; Hewitt, Amy; Leiter, James C.; Erlichman, Joseph S.

doi:10.1016/j.resp.2004.06.014

Cited by 21 publications

(21 citation statements)

References 47 publications

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“…Chemosensitive SC neurons from neonates are preferentially gap junction coupled (7,18) and connexins (the proteins that form gap junctions) are expressed in SC neurons from both neonates and adults (46,48). Carbenoxolone has been shown to effectively uncouple chemosensitive neurons (9) and is used widely to block gap junctions (9,34,39), although it is known to have other effects (36,45,51). We found that HA resulted in a significantly larger membrane depolarization in HA-activated SC neurons from adults in the presence of SNB ϩ CARB (ϳ8 mV) than in aCSF only (ϳ4 mV).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the chemosensitive response of individual solitary complex neurons from adult rats

Nichols¹,

Mulkey²,

Wilkinson³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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(pH i) and electrical responses to hypercapnic acidosis (HA). SC neurons were recorded using the blind whole cell patchclamp technique and loading the soma with the pH-sensitive dye pyranine through the patch pipette. We found that SC neurons from adult rats have a lower steady-state pH i than SC neurons from neonatal rats. In the presence of chemical and electrical synaptic blockade, adult SC neurons have firing rate responses to HA (percentage of neurons activated or inhibited and the magnitude of response as determined by the chemosensitivity index) that are similar to SC neurons from neonatal rats. They also have a typical response to isohydric hypercapnia, including decreased ⌬pHi, followed by pHi recovery, and increased firing rate. Thus, the chemosensitive response of SC neurons from adults is similar to the chemosensitive response of SC neurons from neonatal rats. Because our findings for adults are similar to previously reported values for neurons from neonatal rats, we conclude that intrinsic chemosensitivity is established early in development for SC neurons and is maintained throughout adulthood.

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Section: Discussionmentioning

confidence: 99%

Characterization of the chemosensitive response of individual solitary complex neurons from adult rats

Nichols¹,

Mulkey²,

Wilkinson³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…A 100 M concentration of 4-CIN should inhibit monocarboxylate transport by MCT1 and MCT4 by Ͻ13% while eliminating monocarboxylate transport by MCT2 (100 M 4-CIN is approximately four times the IC 50 MCT2). In the in vivo experiments, we focally perfused the RTN unilaterally with normal aCSF (pH 7.48) or aCSF plus 100 M 4-CIN to determine whether inhibition of MCT2 increased ventilation at each level of CO 2 tested Parisian et al, 2004). Each perfusate was tested on a separate day, and at least 1 d separated each perfusate trial.…”

Section: Methodsmentioning

confidence: 99%

“…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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“…There is evidence of a developmental decline in the contribution of gap junctions to hypercapnic ventilatory responses to CO 2 in the RTN in animals older than 10 weeks of age Parisian et al, 2004). We suspect that part of the early decline in CO 2 sensitivity may reflect the initial loss of gap junctional connectivity among CO 2 -sensitive neurons although this has not been studied explicitly in very young animals.…”

Section: Development Of Brainstem Neurons and Synaptogenesismentioning

confidence: 97%

“…Thus, even though gap junctions coordinate or amplify the output of a set of neurons, the net effect may still be inhibitory. Nonetheless, disruption of gap junctions in animals aged 7-9 weeks was associated with a blunted ventilatory response to CO 2 Parisian et al, 2004). There are no studies analyzing the role of gap junctions in intact rat pups, but it seems likely that gap junctions between CO 2 -sensitive cells augment the respiratory response to CO 2 even in these very young animals, since gap junctions are clearly and preferentially present between CO2-sensitive cells in the NTS at a young age Huang et al, 1997).…”

Section: Development Of Brainstem Neurons and Synaptogenesismentioning

confidence: 98%

Neonatal maturation of the hypercapnic ventilatory response and central neural CO2 chemosensitivity

Putnam

Conrad

Gdovin

et al. 2005

Respiratory Physiology & Neurobiology

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The ventilatory response to CO 2 changes as a function of neonatal development. In rats, a ventilatory response to CO 2 is present in the first 5 days of life, but this ventilatory response to CO 2 wanes and reaches its lowest point around postnatal day 8. Subsequently, the ventilatory response to CO 2 rises towards adult levels. Similar patterns in the ventilatory response to CO 2 are seen in some other species, although some animals do not exhibit all of these phases. Different developmental patterns of the ventilatory response to CO 2 may be related to the state of development of the animal at birth. The triphasic pattern of responsiveness (early decline, a nadir, and subsequent achievement of adult levels of responsiveness) may arise from the development of several processes, including central neural mechanisms, gas exchange, the neuromuscular junction, respiratory muscles and respiratory mechanics. We only discuss central neural mechanisms here, including altered CO 2 sensitivity of neurons among the various sites of central CO 2 chemosensitivity, changes in astrocytic function during development, the maturation of electrical and chemical synaptic mechanisms (both inhibitory and excitatory mechanisms) or changes in the integration of chemosensory information originating from peripheral and multiple central CO 2 chemosensory sites. Among these central processes, the maturation of synaptic mechanisms seems most important and the relative maturation of synaptic processes may also determine how plastic the response to CO 2 is at any particular age.

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

Cited by 21 publications

References 47 publications

Characterization of the chemosensitive response of individual solitary complex neurons from adult rats

Characterization of the chemosensitive response of individual solitary complex neurons from adult rats

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

Neonatal maturation of the hypercapnic ventilatory response and central neural CO2 chemosensitivity

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