Role of the K+-Cl– Cotransporter KCC2a Isoform in Mammalian Respiration at Birth
eNeuro. 2018-01-01; 5(5): ENEURO.0264-18.2018
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1. eNeuro. 2018 Oct 23;5(5). pii: ENEURO.0264-18.2018. doi:
10.1523/ENEURO.0264-18.2018. eCollection 2018 Sep-Oct.
Role of the K+-Cl- Cotransporter KCC2a Isoform in Mammalian Respiration at Birth.
Dubois CJ(1), Cardoit L(1), Schwarz V(1), Markkanen M(2), Airaksinen MS(2),
Uvarov P(2), Simmers J(1), Thoby-Brisson M(1).
(1)Institut de Neurosciences Cognitives et Intégratives D’Aquitaine, CNRS UMR
5287, Université de Bordeaux, Bordeaux 33076, France.
(2)Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki
In central respiratory circuitry, synaptic excitation is responsible for
synchronizing neuronal activity in the different respiratory rhythm phases,
whereas chloride-mediated inhibition is important for shaping the respiratory
pattern itself. The potassium chloride cotransporter KCC2, which serves to
maintain low intraneuronal Cl- concentration and thus render chloride-mediated
synaptic signaling inhibitory, exists in two isoforms, KCC2a and KCC2b. KCC2 is
essential for functional breathing motor control at birth, but the specific
contribution of the KCC2a isoform remains unknown. Here, to address this issue,
we investigated the respiratory phenotype of mice deficient for KCC2a. In vivo
plethysmographic recordings revealed that KCC2a-deficient pups at P0 transiently
express an abnormally low breathing rate and a high occurrence of apneas.
Immunostainings confirmed that KCC2a is normally expressed in the brainstem
neuronal groups involved in breathing (pre-Bötzinger complex, parafacial
respiratory group, hypoglossus nucleus) and is absent in these regions in the
KCC2a-/- mutant. However, in variously reduced in vitro medullary preparations,
spontaneous rhythmic respiratory activity is similar to that expressed in
wild-type preparations, as is hypoglossal motor output, and no respiratory pauses
are detected, suggesting that the rhythm-generating networks are not
intrinsically affected in mutants at P0. In contrast, inhibitory neuromodulatory
influences exerted by the pons on respiratory rhythmogenesis are stronger in the
mutant, thereby explaining the breathing anomalies observed in vivo. Thus, our
results indicate that the KCC2a isoform is important for establishing proper
breathing behavior at the time of birth, but by acting at sites that are
extrinsic to the central respiratory networks themselves.