In vivo evidence for the cellular basis of central hypoventilation of Rett syndrome and pharmacological correction in the rat model. Issue 12 (2nd June 2021)

• Record Type: Journal Article
• Authors: Wu, Yang; Cui, Ningren; Xing, Hao; Zhong, Weiwei; Arrowood, Colin; Johnson, Christopher M.; Jiang, Chun
• Is Part Of: Journal of cellular physiology. Volume 236:Issue 12(2021)
• Page Start: 8082
• Page End: 8098
• Publication Date: 2021-06-02
• Subjects: apnea -- GABAergic inhibition -- medullary respiratory neurons -- phrenic activity -- Rett syndrome -- therapeutic intervention; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.30462
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by mutations in the MECP2 gene. RTT patients show periodical hypoventilation attacks. The breathing disorder contributing to the high incidence of sudden death is thought to be due to depressed central inspiratory (I) activity via unknown cellular processes. Demonstration of such processes may lead to targets for pharmacological control of the RTT‐type hypoventilation. We performed in vivo recordings from medullary respiratory neurons on the RTT rat model. To our surprise, both I and expiratory (E) neurons in the ventral respiratory column (VRC) increased their firing activity in Mecp2 ‐null rats with severe hypoventilation. These I neurons including E–I phase‐spanning and other I neurons remained active during apneas. Consistent with enhanced central I drive, ectopic phrenic discharges during expiration as well as apnea were observed in the Mecp2 ‐null rats. Considering the increased I neuronal firing and ectopic phrenic activity, the RTT‐type hypoventilation does not seem to be caused by depression in central I activity, neither reduced medullary I premotor output. This as well as excessive E neuronal firing as shown in our previous studies suggests inadequate synaptic inhibition for phase transition. We found that the abnormal respiratory neuronal firing, ectopic phrenic discharge as well as RTT‐type hypoventilation all can be corrected by enhancing GABAergic inhibition. More strikingly, Mecp2 ‐null rats reaching humane endpoints with severe hypoventilation can be rescued by GABAergic augmentation. Thus, defective GABAergic inhibition among respiratory neurons is likely to play a role in the RTT‐type hypoventilation, which can be effectively controlled with pharmacological agents. Abstract : Highlights: Activity of inspiratory neurons in VRC increased in Mecp2 ‐null rats. Many of these inspiratory neurons remained firing during apneas. Bulbospinal neurons with E–I patterns contribute to ectopic phrenic discharges. GABAergic agents reduced the abnormal neuronal discharges and hypoventilation. GABAergic agents rescued dying Mecp2 ‐null rat accompanied by breathing improvement.