The role of PHOX2B‐derived astrocytes in chemosensory control of breathing and sleep homeostasis

Abstract

Key points The embryonic PHOX2B‐progenitor domain generates neuronal and glial cells which together are involved in chemosensory control of breathing and sleep homeostasis. Ablating PHOX2B‐derived astrocytes significantly contributes to secondary hypoxic respiratory depression as well as abnormalities in sleep homeostasis. PHOX2B‐derived astrocyte ablation results in axonal pathologies in the retrotrapezoid nucleus. Abstract We identify in mice a population of ∼800 retrotrapezoid nucleus (RTN) astrocytes derived from PHOX2B‐positive, OLIG3‐negative progenitor cells, that interact with PHOX2B‐expressing RTN chemosensory neurons. PHOX2B‐derived astrocyte ablation during early life results in adult‐onset O2 chemoreflex deficiency. These animals also display changes in sleep homeostasis, including fragmented sleep and disturbances in delta power after sleep deprivation, all without observable changes in anxiety or social behaviours. Ultrastructural evaluation of the RTN demonstrates that PHOX2B‐derived astrocyte ablation results in features characteristic of degenerative neuro‐axonal dystrophy, including abnormally dilated axon terminals and increased amounts of synapses containing autophagic vacuoles/phagosomes. We conclude that PHOX2B‐derived astrocytes are necessary for maintaining a functional O2 chemosensory reflex in the adult, modulate sleep homeostasis, and are key regulators of synaptic integrity in the RTN region, which is necessary for the chemosensory control of breathing. These data also highlight how defects in embryonic development may manifest as neurodegenerative pathology in an adult.

Research Advances on Therapeutic Approaches to Congenital Central Hypoventilation Syndrome (CCHS)

“…Recently, the role of astrocytes in the chemosensitive response (paracrine hypothesis) has been postulated ( Guyenet et al, 2019 , and references therein). In particular, it has been reported that PHOX2B-derived astrocytes play a role in chemosensory control of breathing ( Czeisler et al, 2019 ), especially in the adult, by maintaining a functional O 2 chemosensitive response, adequate sleep homeostasis and by ensuring synaptic integrity of neurons in RTN. It is then plausible to hypothesize that PHOX2B mutations may have consequences also in the development of this group of astrocytes.…”

Neonatal apneic phenotype in a murine congenital central hypoventilation syndrome model is induced through non‐cell autonomous developmental mechanisms

“…Note that the cholinergic cells of the nVII cranial nerve showed GFP expression in this animal, indicating that nVII neurons are derived from progenitor cells that express Nkx2.2 and Phox2b (Figure 5A,B). However, in the RTN, small neurons at the ventral surface show tdTomato expression (Figure 5C3 arrow), whereas a subset of RTN astrocytes show dual derivation of Nkx2.2 and Phox2b (10). In the caudal medulla, the dorsal motor nucleus of the vagus nerve (DMNV) and nucleus ambiguus (Figure 5E‐F), a well‐characterized Phox2b ‐expressing neuron cluster (33), shows derivation from both Phox2b and Nkx2.2 ‐expressing progenitor cells.…”

Breathing Behaviors in Common Marmoset (Callithrix jacchus)

“…The mechanism of hypoxic ventilatory decline (HVD) is not fully understood. It is proposed that desensitization of peripheral chemoreceptors might have a role (76), though significant evidence suggest that, at least in rodents, astrocytes (the numerous star-shaped glia cells) in preBötC (6,8,77) and RTN (78,79) are capable of acting as central respiratory oxygen chemosensors and contribute to the HVD possibly via vesicular release of adenosine triphosphate (ATP). In addition to preBötC and RTN, rostral ventrolateral medulla (rVLM) and the nucleus of the solitary tract (NTS) in the brainstem are proposed to have oxygen sensing capabilities (80,81).…”