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Fractalkine signaling in the cervical spinal cord orchestrates microglia‐neuron interactions regulating intermittent hypoxia‐induced phrenic motor plasticity
Author(s) -
Tadjalli Arash,
Baker Tracy,
Watters Jyoti,
Mitchell Gordon
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02364
Subject(s) - cx3cr1 , microglia , neuroscience , adenosine , intermittent hypoxia , biology , hypoxia (environmental) , motor neuron , neuroplasticity , spinal cord , central nervous system , medicine , inflammation , immunology , chemokine , anesthesia , chemistry , chemokine receptor , endocrinology , organic chemistry , oxygen , obstructive sleep apnea
Microglia are innate immune cells with many non‐immune functions in the healthy nervous system. For example, microglia engage in bidirectional communication with central nervous system neurons, regulating diverse processes including neuronal architecture, excitability, and synaptic plasticity. Although neuron‐microglia interactions are known to regulate several forms of neuroplasticity, their role in regulating respiratory motor plasticity is unknown. Acute intermittent hypoxia (AIH) elicits a form of plasticity in the phrenic motor system known as phrenic long‐term facilitation (pLTF) — a progressive, long‐lasting increase in phrenic motor output following AIH. Whereas AIH consisting of moderate hypoxic episodes elicits pLTF by a serotonin‐dependent, adenosine‐constrained mechanism, severe AIH elicits pLTF by an adenosine‐dominant mechanism. Here, we test the hypothesis that communication between cervical spinal neurons and microglia differentially regulates moderate versus severe AIH‐induced pLTF. Specifically, we hypothesized that neuron‐microglia signaling modulates pLTF expression by: 1) neuronal fractalkine (CX3CL1) release and activation of its receptor, CX3CR1, which is uniquely expressed in CNS microglia; and 2) fractalkine‐induced ATP release, and breakdown to adenosine, which differentially regulates moderate and severe AIH‐induced pLTF. In anesthetized, adult male Sprague Dawley rats, cervical spinal CX3CR1 inhibition enhanced serotonin‐dependent moderate AIH‐induced pLTF, but blocked adenosine‐dependent, severe AIH‐induced pLTF. Further, spinal CX3CR1 activation with recombinant fractalkine induced phrenic motor facilitation in a dose‐dependent manner— an effect that required both cervical spinal ATP breakdown and adenosine 2A receptor activation. We thus propose a hypothetical model whereby hypoxia triggers dose‐dependent phrenic motor neuron fractalkine release that activates CX3CR1 on nearby microglia. Subsequent microglial ATP release and eventual breakdown increases extracellular adenosine and undermines serotonin‐dependent pLTF, but drives severe AIH‐induced (adenosine‐dependent) pLTF by activating phrenic motor neuron adenosine 2A receptors. These findings enhance our understanding of how spinal, intercellular interactions regulate AIH‐induced plasticity in the phrenic motor circuit.