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Daily isoflurane exposure increases barbiturate insensitivity in medullary respiratory and cortical neurons via expression of ε-subunit containing GABA ARs.

Hengen KB, Nelson NR, Stang KM, Johnson SM, Smith SM, Watters JJ, Mitchell GS, Behan M - PLoS ONE (2015)

Bottom Line: The parameters governing GABAA receptor subtype expression patterns are not well understood, although significant shifts in subunit expression may support key physiological events.We hypothesized that this plasticity may be a compensatory response to a chronic increase in inhibitory tone caused by increased central neurosteroid levels.We hypothesize that increased inhibitory tone in the respiratory control network and cortex causes a compensatory increase in ε-subunit-containing GABAARs.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Training Program, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.

ABSTRACT
The parameters governing GABAA receptor subtype expression patterns are not well understood, although significant shifts in subunit expression may support key physiological events. For example, the respiratory control network in pregnant rats becomes relatively insensitive to barbiturates due to increased expression of ε-subunit-containing GABAARs in the ventral respiratory column. We hypothesized that this plasticity may be a compensatory response to a chronic increase in inhibitory tone caused by increased central neurosteroid levels. Thus, we tested whether increased inhibitory tone was sufficient to induce ε-subunit upregulation on respiratory and cortical neurons in adult rats. Chronic intermittent increases in inhibitory tone in male and female rats was induced via daily 5-min exposures to 3% isoflurane. After 7d of treatment, phrenic burst frequency was less sensitive to barbiturate in isoflurane-treated male and female rats in vivo. Neurons in the ventral respiratory group and cortex were less sensitive to pentobarbital in vitro following 7d and 30d of intermittent isoflurane-exposure in both male and female rats. The pentobarbital insensitivity in 7d isoflurane-treated rats was reversible after another 7d. We hypothesize that increased inhibitory tone in the respiratory control network and cortex causes a compensatory increase in ε-subunit-containing GABAARs.

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Increased GABAAR ε subunit mRNA levels in medulla and cortex in 30d isoflurane-treated rats.Medullary GABAAR ε mRNA levels were more than 3-fold greater in 30d isoflurane-treated rats compared to untreated control rats. Likewise, cortical GABAAR ε mRNA levels were more than 4-fold increased in 30d isoflurane-treated rats. Statistics were conducted on delta CT values. Asterisk denotes p<0.05. Error bars indicate SEM.
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pone.0119351.g004: Increased GABAAR ε subunit mRNA levels in medulla and cortex in 30d isoflurane-treated rats.Medullary GABAAR ε mRNA levels were more than 3-fold greater in 30d isoflurane-treated rats compared to untreated control rats. Likewise, cortical GABAAR ε mRNA levels were more than 4-fold increased in 30d isoflurane-treated rats. Statistics were conducted on delta CT values. Asterisk denotes p<0.05. Error bars indicate SEM.

Mentions: To quantify whether intermittent isoflurane treatment altered the transcriptional regulation of the GABAAR ε subunit, cortical and medullary samples from 30d isoflurane-treated rats (n = 5) and untreated control rats (n = 12) were harvested for GABAAR ε subunit mRNA analysis (Fig. 4). The 30d isoflurane treatment increased GABAAR ε subunit mRNA in medullary samples compared to untreated samples (3.9 ± 1.39-fold increase, p<0.05). Cortical samples from 30d isoflurane-treated rats also demonstrated increased GABAAR ε subunit mRNA levels compared to controls (4.2 ± 1.35-fold increase, p<0.05, Wilcoxon Rank Sum). These data demonstrate a correlation between the emergence of barbiturate-insensitive GABAARs in VRC and cortex and the transcriptional upregulation of GABAAR ε subunit mRNA.


Daily isoflurane exposure increases barbiturate insensitivity in medullary respiratory and cortical neurons via expression of ε-subunit containing GABA ARs.

Hengen KB, Nelson NR, Stang KM, Johnson SM, Smith SM, Watters JJ, Mitchell GS, Behan M - PLoS ONE (2015)

Increased GABAAR ε subunit mRNA levels in medulla and cortex in 30d isoflurane-treated rats.Medullary GABAAR ε mRNA levels were more than 3-fold greater in 30d isoflurane-treated rats compared to untreated control rats. Likewise, cortical GABAAR ε mRNA levels were more than 4-fold increased in 30d isoflurane-treated rats. Statistics were conducted on delta CT values. Asterisk denotes p<0.05. Error bars indicate SEM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352015&req=5

pone.0119351.g004: Increased GABAAR ε subunit mRNA levels in medulla and cortex in 30d isoflurane-treated rats.Medullary GABAAR ε mRNA levels were more than 3-fold greater in 30d isoflurane-treated rats compared to untreated control rats. Likewise, cortical GABAAR ε mRNA levels were more than 4-fold increased in 30d isoflurane-treated rats. Statistics were conducted on delta CT values. Asterisk denotes p<0.05. Error bars indicate SEM.
Mentions: To quantify whether intermittent isoflurane treatment altered the transcriptional regulation of the GABAAR ε subunit, cortical and medullary samples from 30d isoflurane-treated rats (n = 5) and untreated control rats (n = 12) were harvested for GABAAR ε subunit mRNA analysis (Fig. 4). The 30d isoflurane treatment increased GABAAR ε subunit mRNA in medullary samples compared to untreated samples (3.9 ± 1.39-fold increase, p<0.05). Cortical samples from 30d isoflurane-treated rats also demonstrated increased GABAAR ε subunit mRNA levels compared to controls (4.2 ± 1.35-fold increase, p<0.05, Wilcoxon Rank Sum). These data demonstrate a correlation between the emergence of barbiturate-insensitive GABAARs in VRC and cortex and the transcriptional upregulation of GABAAR ε subunit mRNA.

Bottom Line: The parameters governing GABAA receptor subtype expression patterns are not well understood, although significant shifts in subunit expression may support key physiological events.We hypothesized that this plasticity may be a compensatory response to a chronic increase in inhibitory tone caused by increased central neurosteroid levels.We hypothesize that increased inhibitory tone in the respiratory control network and cortex causes a compensatory increase in ε-subunit-containing GABAARs.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Training Program, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.

ABSTRACT
The parameters governing GABAA receptor subtype expression patterns are not well understood, although significant shifts in subunit expression may support key physiological events. For example, the respiratory control network in pregnant rats becomes relatively insensitive to barbiturates due to increased expression of ε-subunit-containing GABAARs in the ventral respiratory column. We hypothesized that this plasticity may be a compensatory response to a chronic increase in inhibitory tone caused by increased central neurosteroid levels. Thus, we tested whether increased inhibitory tone was sufficient to induce ε-subunit upregulation on respiratory and cortical neurons in adult rats. Chronic intermittent increases in inhibitory tone in male and female rats was induced via daily 5-min exposures to 3% isoflurane. After 7d of treatment, phrenic burst frequency was less sensitive to barbiturate in isoflurane-treated male and female rats in vivo. Neurons in the ventral respiratory group and cortex were less sensitive to pentobarbital in vitro following 7d and 30d of intermittent isoflurane-exposure in both male and female rats. The pentobarbital insensitivity in 7d isoflurane-treated rats was reversible after another 7d. We hypothesize that increased inhibitory tone in the respiratory control network and cortex causes a compensatory increase in ε-subunit-containing GABAARs.

Show MeSH
Related in: MedlinePlus