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Defective microglia alters respiratory control and mitochondrial function in mice.
Author(s) -
Rousseau JeanPhilippe,
Laouafa Sofien,
Tremblay MarieÈve,
Joseph Vincent,
Kinkead Richard
Publication year - 2017
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.31.1_supplement.1010.2
Subject(s) - brainstem , respiratory system , respiration , chemistry , medicine , endocrinology , chemoreceptor , biology , anatomy , receptor
We tested the hypothesis that alteration of microglial function impairs respiratory control and mitochondrial function in the brainstem of newborn mice. Measurements were performed on newborn CX3CR1 knockout (fractalkine receptor deficient) and control (C57Bl6) mice aged of 1 day. Fictive breathing (in‐vitro) was measured by extracting the brainstem with a part of the spinal cord and placing it in a chamber where it was superfused with an artificial cerebrospinal fluid (aCSF). The output signal from the respiratory network was recorded by a suction electrode placed on the fourth ventral root (C4) representing the inspiratory signal sent to the diaphragm via the phrenic nerve. Mitochondrial function was assessed on fresh brainstem tissue (~4–5 mg) permeabilized with saponin using high‐resolution oxygraph ( O2k‐Oroboros ) allowing to evaluate simultaneously O 2 consumption and H 2 O 2 production (reflect of reactive oxygen species). Compared to controls, CX3CR1 KO mice showed 41% decreased phrenic burst frequency under baseline conditions (3.0±1.2 vs 7.3±1.0 bursts/min; P<0.05). O 2 consumption measurements under basal condition with substrates of complex I (Pyruvate/Malate) and complex II (Succinate) showed no effects between control and CX3CR1 KO (CI: 5.8±0.4 vs 3.9±0.5 pmol O 2 /s/mg; CII: 10±0.3 vs 7.8±0.6 pmol O 2 /s/mg). However, addition of ADP stimulated mitochondrial respiratory chain and increased O 2 consumption in control more than CX3CR1 KO mice with substrate of complex I (29.4±2.6 vs 22.3 ±1 pmol O 2 /s/mg; P<0.01), complex II (39.5±1 vs 31±1.5 pmol O 2 /s/mg; P<0.005) and complex I+II (55.5±2.1 vs 41.4±1.4 pmol O 2 /s/mg; P<0.0001). Moreover, H 2 O 2 production tends to increase in CX3CR1 KO mice compared to control with substrates of complexes I and II under stimulation by ADP. We can conclude that CX3CR1 KO mice exhibit an alteration of respiratory control as well as a mitochondrial dysfunction. These preliminary results provide new hypotheses regarding the origins of respiratory disorders of the newborn involving reduced respiratory drive such as apnea of prematurity. Support or Funding Information Founded by NSERC, Région Rhône‐Alpes and consulat de France à Québec.