Abdominal expiratory activity in the rat brainstem–spinal cord <i>in situ</i>: patterns, origins and implications for respiratory rhythm generation

Abdala, Ana Paula; Rybak, Ilya A.; Smith, Jeffrey C.; Paton, Julian F. R.

doi:10.1113/jphysiol.2008.167502

Cited by 176 publications

(385 citation statements)

References 50 publications

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“…In this in situ preparation, CO 2 and bicarbonate levels in the brainstem perfusate are controlled and phrenic nerve activity serves as a measure of central respiratory outflow. As reported previously (Abdala et al, 2009;Marina et al, 2010), we found that respiratory acidosis evoked by increasing inspired CO 2 from 5 to 7 or 9% caused an increase in phrenic burst amplitude with little effect on phrenic burst frequency (Fig. 6A-C).…”

Section: Task-2 Channels Are Required For Ph Sensitivity In Those Rtnsupporting

confidence: 70%

TASK-2 Channels Contribute to pH Sensitivity of Retrotrapezoid Nucleus Chemoreceptor Neurons

et al. 2013

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Phox2b-expressing glutamatergic neurons of the retrotrapezoid nucleus (RTN) display properties expected of central respiratory chemoreceptors; they are directly activated by CO 2 /Hϩ via an unidentified pH-sensitive background K ϩ channel and, in turn, facilitate brainstem networks that control breathing. Here, we used a knock-out mouse model to examine whether TASK-2 (K2P5), an alkaline-activated background K ϩ channel, contributes to RTN neuronal pH sensitivity. We made patch-clamp recordings in brainstem slices from RTN neurons that were identified by expression of GFP (directed by the Phox2b promoter) or ␤-galactosidase (from the gene trap used for TASK-2 knock-out). Whereas nearly all RTN cells from control mice were pH sensitive (95%, n ϭ 58 of 61), only 56% of GFP-expressing RTN neurons from TASK-2 Ϫ/Ϫ mice (n ϭ 49 of 88) could be classified as pH sensitive (Ͼ30% reduction in firing rate from pH 7.0 to pH 7.8); the remaining cells were pH insensitive (44%). Moreover, none of the recorded RTN neurons from TASK-2 Ϫ/Ϫ mice selected based on ␤-galactosidase activity (a subpopulation of GFP-expressing neurons) were pH sensitive. The alkaline-activated background K ϩ currents were reduced in amplitude in RTN neurons from TASK-2 Ϫ/Ϫ mice that retained some pH sensitivity but were absent from pH-insensitive cells. Finally, using a working heart-brainstem preparation, we found diminished inhibition of phrenic burst amplitude by alkalization in TASK-2 Ϫ/Ϫ mice, with apneic threshold shifted to higher pH levels. In conclusion, alkaline-activated TASK-2 channels contribute to pH sensitivity in RTN neurons, with effects on respiration in situ that are particularly prominent near apneic threshold.

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Section: Task-2 Channels Are Required For Ph Sensitivity In Those Rtnsupporting

confidence: 70%

TASK-2 Channels Contribute to pH Sensitivity of Retrotrapezoid Nucleus Chemoreceptor Neurons

et al. 2013

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“…In addition, there is evidence that medullary sites also play a role. Bilateral microinjections of the GABA A agonist isoguvacine into retrotrapezoid nucleus (RTN) reduced post-I in cVN (15). This indicates that RTN either through afferents to KF or as a relay from KF to post-I neurons in the Bötzinger complex plays an important role in the generation of post-I expression.…”

Section: Insufficient Gaba a Inhibition Underlies Tonic Activity In Ementioning

confidence: 99%

“…The tonic AbN seen in Mecp2 −/+ mice during PN apnea has a similar, albeit prolonged, pattern. Either pontine transection or bilateral isoguvacine injections into RTN abolished late-E AbN activity (15), and on the basis of this we propose that these regions could generate the pathological discharge in the abdominal motor outflow in Mecp2 −/+ mice.…”

Section: Insufficient Gaba a Inhibition Underlies Tonic Activity In Ementioning

confidence: 99%

“…1 B, arrow, and D). The association of tonic HN with that in AbN, an expiratory nerve (15), and with postinspiration in cVN suggests that it is the expiratory component of HN that tonically discharges in PN apnea. The duration of apnea in Mecp2 −/+ (2.82 ± 0.16 s) exceeded that in WT (1.96 ± 0.12 s) (P = 0.0004, unpaired t test).…”

Section: Characterization Of Apnea In Heterozygous Mecp2-deficient Fementioning

confidence: 99%

“…Recently, expiratory activity in the AbN has been well characterized in neonatal and juvenile rats examined with the in situ preparation (15). Under baseline conditions (5% CO 2 ) only post-I discharge was present.…”

Section: Insufficient Gaba a Inhibition Underlies Tonic Activity In Ementioning

confidence: 99%

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Correction of respiratory disorders in a mouse model of Rett syndrome

Abdala

Dutschmann

Bissonnette

et al. 2010

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

148

159

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Rett syndrome (RTT) is an autism spectrum disorder caused by mutations in the X-linked gene that encodes the transcription factor methyl-CpG-binding protein 2 (MeCP2). A major debilitating phenotype in affected females is frequent apneas, and heterozygous Mecp2-deficient female mice mimic the human respiratory disorder. GABA defects have been demonstrated in the brainstem of Mecp2-deficient mice. Here, using an intact respiratory network, we show that apnea in RTT mice is characterized by excessive excitatory activity in expiratory cranial and spinal nerves. Augmenting GABA markedly improves the respiratory phenotype. In addition, a serotonin 1a receptor agonist that depresses expiratory neuron activity also reduces apnea, corrects the irregular breathing pattern, and prolongs survival in MeCP2 null males. Combining a GABA reuptake blocker with a serotonin 1a agonist in heterozygous females completely corrects their respiratory defects. The results indicate that GABA and serotonin 1a receptor activity are candidates for treatment of the respiratory disorders in Rett syndrome.R ett syndrome (RTT) is an autism spectrum disorder that is caused by mutations in the X-linked gene that encodes methyl-CpG-binding protein 2 (MeCP2) (1). The role of this transcription factor is incompletely understood. Until recently, on the basis of animal studies primarily in embryonic or early neonatal brain, Mecp2 was considered a translational repressor (2, 3). Recently, however, Skene et al. (4) found in neuronal nuclei of mature (6-8 wk) WT littermates of Mecp2 null males that Mecp2 expression is ≈fivefold greater than that at birth. The amount of Mecp2 bound to DNA was proportional to the methylation density of CpG sequences. Importantly, in adult mice, it has been shown that restoring Mecp2 reverses the abnormalities in mobility, gait, hind limb clasping, tremor, breathing, and general condition that they developed during the period that the transcription factor was deficient (5). Thus, Mecp2 deficiency does not cause neuronal degeneration, nor is it necessary for the correct development of neuronal networks. Strategies aimed at pharmacological corrections of symptoms are therefore essential in treating RTT.Respiratory disorders are prominent and one of the most disturbing features of RTT (6, 7). These abnormalities are faithfully mimicked in mouse models of RTT (8). In Mecp2 null male animals studied in situ phrenic (PN) apneas were characterized by prolonged postinspiratory (post-I) activity in the central vagus nerve (9). Post-I activity is linked to the control of laryngeal adductors that control expiratory airflow and protect the lower airways from aspiration during swallowing. Active breath-hold with laryngeal closure is a common feature of RTT (6,7,10).This raises the possibility that the apneas are due to overactive brainstem expiratory neurons in Mecp2 heterozygote mice, perhaps consequent to a lack of synaptic inhibitory control. In this regard, examination of GABA synaptic inhibition in the ventrolateral medulla of Mec...

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Projections of preBötzinger Complex neurons in adult rats

Tan

Pagliardini

Yang

et al. 2010

J of Comparative Neurology

124

130

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The preBötzinger Complex (preBötC) contains neural microcircuitry essential for normal respiratory rhythm generation in rodents. A subpopulation of preBötC neurons expresses somatostatin, a neuropeptide with a modulatory action on breathing. Acute silencing of a subpopulation of preBötC neurons transfected by a virus driving protein expression under the somatostatin promoter results in persistent apnea in awake adult rats. Given the profound effect of silencing these neurons, their projections are of interest. We used an adeno-associated virus to overexpress enhanced green fluorescent protein driven by the somatostatin promoter in preBötC neurons to label their axons and terminal fields. These neurons send brainstem projections to: 1) contralateral preBötC; 2) ipsi- and contralateral Bötzinger Complex; 3) ventral respiratory column caudal to preBötC; 4) parafacial respiratory group / retrotrapezoid nucleus; 5) parahypoglossal nucleus/nucleus of the solitary tract; 6) parabrachial/Kölliker-Fuse nuclei; and 7) periaqueductal gray. We did not find major projections to either cerebellum or spinal cord. We conclude that there are widespread projections from preBötC somatostatin-expressing neurons specifically targeted to brainstem regions implicated in control of breathing, and provide a network basis for the profound effects and the essential role of the preBötC in breathing.

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Abdominal expiratory activity in the rat brainstem–spinal cord in situ: patterns, origins and implications for respiratory rhythm generation

Cited by 176 publications

References 50 publications

TASK-2 Channels Contribute to pH Sensitivity of Retrotrapezoid Nucleus Chemoreceptor Neurons

TASK-2 Channels Contribute to pH Sensitivity of Retrotrapezoid Nucleus Chemoreceptor Neurons

Correction of respiratory disorders in a mouse model of Rett syndrome

Projections of preBötzinger Complex neurons in adult rats

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