Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (UMR5287)

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Mammalian respiration at birth

by Wolff - published on

Mammalian respiration at birth

Role of the K+-Cl– Cotransporter KCC2a Isoform in Mammalian Respiration at Birth
Christophe J. Dubois, Laura Cardoit, Veronika Schwarz, Marika Markkanen, Matti S.
Airaksinen, Pavel Uvarov, John Simmers, and Muriel Thoby-Brisson

In this study, researchers from the OASM team together with colleagues from Finland investigated the role of a specific isoform of the chloride co-transporter KCC2 (KCC2a isoform) in the proper establishment of the central respiratory command during development. In the respiratory neural networks, inhibitory synaptic transmission plays an important role in pattern formation, regulation of neuronal excitability and apneas generation. Therefore, disturbances in the chloride-mediated signaling, involving chloride co-transporters (such as NKCC and KCC), might have important consequences into the functioning of the respiratory networks. Using a mouse line deleted specifically for the KCC2a isoform they observed that mutant transiently exhibit respiratory anomalies at the time of birth, including a lower breathing frequency and an abnormally high occurrence of apneas. These defaults, mainly detectable at P0 (day of birth), are associated with a dysfunction in the pontine regulatory neuronal groups rather than in neurons of the respiratory rhythm generator circuits per se. Because pontine influences are mostly inhibitory, these results suggest that, in the mutant, excessive modulation exerted by pontine neurons onto respiratory neurons is responsible for the slower breathing frequency and facilitates the occurrence of apneas. Thus, it is concluded that the KCC2a isoform plays an important role in ensuring the correct expression of respiratory rhythmogenesis at the time of birth.

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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.