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AbstractBreathing behaviour involves the generation of normal breaths (eupnoea) on a timescale of seconds and sigh breaths on the order of minutes. Both rhythms emerge in tandem from a single brainstem site, but whether and how a single cell population can generate two disparate rhythms remains unclear. We posit that recurrent synaptic excitation in concert with synaptic depression and cellular refractoriness gives rise to the eupnoea rhythm, whereas an intracellular calcium oscillation that is slower by orders of magnitude gives rise to the sigh rhythm. A mathematical model capturing these dynamics simultaneously generates eupnoea and sigh rhythms with disparate frequencies, which can be separately regulated by physiological parameters. We experimentally validated key model predictions regarding intracellular calcium signalling. All vertebrate brains feature a network oscillator that drives the breathing pump for regular respiration. However, in air‐breathing mammals with compliant lungs susceptible to collapse, the breathing rhythmogenic network may have refashioned ubiquitous intracellular signalling systems to produce a second slower rhythm (for sighs) that prevents atelectasis without impeding eupnoea.image Key pointsA simplified activity‐based model of the preBötC generates inspiratory and sigh rhythms from a single neuron population.Inspiration is attributable to a canonical excitatory network oscillator mechanism.Sigh emerges from intracellular calcium signalling.The model predicts that perturbations of calcium uptake and release across the endoplasmic reticulum counterintuitively accelerate and decelerate sigh rhythmicity, respectively, which was experimentally validated.Vertebrate evolution may have adapted existing intracellular signalling mechanisms to produce slow oscillations needed to optimize pulmonary function in mammals.
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Tonic extracellular glutamate and ischaemia: glutamate antiporter system x c − regulates anoxic depolarization in hippocampus
AbstractIn stroke, the sudden deprivation of oxygen to neurons triggers a profuse release of glutamate that induces anoxic depolarization (AD) and leads to rapid cell death. Importantly, the latency of the glutamate‐driven AD event largely dictates subsequent tissue damage. Although the contribution of synaptic glutamate during ischaemia is well‐studied, the role of tonic (ambient) glutamate has received far less scrutiny. The majority of tonic, non‐synaptic glutamate in the brain is governed by the cystine/glutamate antiporter, system xc−. Employing hippocampal slice electrophysiology, we showed that transgenic mice lacking a functional system xc−display longer latencies to AD and altered depolarizing waves compared to wild‐type mice after total oxygen deprivation. Experiments which pharmacologically inhibited system xc−, as well as those manipulating tonic glutamate levels and those antagonizing glutamate receptors, revealed that the antiporter's putative effect on ambient glutamate precipitates the ischaemic cascade. As such, the current study yields novel insight into the pathogenesis of acute stroke and may direct future therapeutic interventions.image Key pointsIschaemic stroke remains the leading cause of adult disability in the world, but efforts to reduce stroke severity have been plagued by failed translational attempts to mitigate glutamate excitotoxicity.Elucidating the ischaemic cascade, which within minutes leads to irreversible tissue damage induced by anoxic depolarization, must be a principal focus.Data presented here show that tonic, extrasynaptic glutamate supplied by system xc−synergizes with ischaemia‐induced synaptic glutamate release to propagate AD and exacerbate depolarizing waves.Exploiting the role of system xc−and its obligate release of ambient glutamate could, therefore, be a novel therapeutic direction to attenuate the deleterious effects of acute stroke.
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- PAR ID:
- 10383280
- Publisher / Repository:
- Wiley-Blackwell
- Date Published:
- Journal Name:
- The Journal of Physiology
- Volume:
- 601
- Issue:
- 3
- ISSN:
- 0022-3751
- Page Range / eLocation ID:
- p. 607-629
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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