Abstract
GABAergic signaling is essential for proper respiratory function. Potentiation of this signaling with allosteric modulators such as anesthetics, barbiturates, and neurosteroids can lead to respiratory arrest. Paradoxically, pregnant animals continue to breathe normally despite nearly 100-fold increases in circulating neurosteroids. ε subunit-containing GABAARs are insensitive to positive allosteric modulation, thus we hypothesized that pregnant rats increase ε subunit-containing GABAAR expression on brainstem neurons of the ventral respiratory column (VRC). In vivo, pregnancy rendered respiratory motor output insensitive to otherwise lethal doses of pentobarbital, a barbiturate previously used to categorize the ε subunit. Using electrode array recordings in vitro, we demonstrated that putative respiratory neurons of the preBötzinger Complex (preBötC) were also rendered insensitive to the effects of pentobarbital during pregnancy, but unit activity in the VRC was rapidly inhibited by the GABAAR agonist, muscimol. VRC unit activity from virgin and post-partum females was potently inhibited by both pentobarbital and muscimol. Brainstem ε subunit mRNA and protein levels were increased in pregnant rats, and GABAAR ε subunit expression co-localized with a marker of rhythm generating neurons (neurokinin 1 receptors) in the preBötC. These data support the hypothesis that pregnancy renders respiratory motor output and respiratory neuron activity insensitive to barbiturates, most likely via increased ε subunit-containing GABAAR expression on respiratory rhythm-generating neurons. Increased ε subunit expression may be critical to preserve respiratory function (and life) despite increased neurosteroid levels during pregnancy.
Highlights
The control of respiration has long been considered a hardwired, immutable neural network
We examined slices used in in vitro experiments immunohistochemically to confirm that: 1) in vitro recordings were conducted on a population of neurons in three respiratory regions of the ventral respiratory column (VRC) including those believed to be critical for rhythm generation, and 2) the GABAA receptor (GABAAR) e subunit is expressed on putative respiratory neurons in these regions
Phrenic motor output is highly resistant to depression by pentobarbital, a positive allosteric modulator of GABAARs
Summary
The control of respiration has long been considered a hardwired, immutable neural network. Recently has it been demonstrated that the neural control of breathing is highly plastic [1]. Normal breathing requires a complex interplay of excitatory (e.g. glutamate) and inhibitory (e.g. GABA) neurotransmitters, each system providing myriad possibilities for plasticity. Tonic GABAA receptor (GABAAR) activation provides gain modulation of bursting activity in medullary respiratory neurons of the ventral respiratory column (VRC) [3]. Due to their direct impact on the gain control of the respiratory system, allosteric modulators of these GABAARs, including anesthetics, ethanol, endogenous neurosteroids, and many anxiolytics, are often potent respiratory depressants [4,5,6,7]
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