The vesicular glutamate transporter VGLUT3 contributes to protection against neonatal hypoxic stress

Key points •  Hypoxic stress is an important cause of morbidity and mortality in neonates. •  We examined the role of VGLUT3, an atypical transporter of glutamate present in serotonergic neurons involved in breathing and heat production, in the response to hypoxia. •  The respiratory responses to chemical stimuli and the turnover of serotonin in the brainstem were impaired in newborn mice lacking VGLUT3. •  Under cold conditions, metabolic rate, body temperature, baseline breathing and the ventilatory response to hypoxia were disrupted. •  Thus, VGLUT3 expression is required for optimal response to hypoxic stress in neonates. Abstract  Neonates respond to hypoxia initially by increasing ventilation, and then by markedly decreasing both ventilation (hypoxic ventilatory decline) and oxygen consumption (hypoxic hypometabolism). This latter process, which vanishes with age, reflects a tight coupling between ventilatory and thermogenic responses to hypoxia. The neurological substrate of hypoxic hypometabolism is unclear, but it is known to be centrally mediated, with a strong involvement of the 5-hydroxytryptamine (5-HT, serotonin) system. To clarify this issue, we investigated the possible role of VGLUT3, the third subtype of vesicular glutamate transporter. VGLUT3 contributes to glutamate signalling by 5-HT neurons, facilitates 5-HT transmission and is expressed in strategic regions for respiratory and thermogenic control. We therefore assumed that VGLUT3 might significantly contribute to the response to hypoxia. To test this possibility, we analysed this response in newborn mice lacking VGLUT3 using anatomical, biochemical, electrophysiological and integrative physiology approaches. We found that the lack of VGLUT3 did not affect the histological organization of brainstem respiratory networks or respiratory activity under basal conditions. However, it impaired respiratory responses to 5-HT and anoxia, showing a marked alteration of central respiratory control. These impairments were associated with altered 5-HT turnover at the brainstem level. Furthermore, under cold conditions, the lack of VGLUT3 disrupted the metabolic rate, body temperature, baseline breathing and the ventilatory response to hypoxia. We conclude that VGLUT3 expression is dispensable under basal conditions but is required for optimal response to hypoxic stress in neonates.