The vesicular glutamate transporter VGLUT3 contributes to protection against neonatal hypoxic stress.
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.
Institut National de la Santé et de la Recherche Médicale (INSERM), U952, 75005 Paris, France.
Stéphanie
S
Miot
Nicolas
N
Voituron
Adélaïde
A
Sterlin
Erika
E
Vigneault
Lydie
L
Morel
Boris
B
Matrot
Nelina
N
Ramanantsoa
Bénédicte
B
Amilhon
Odile
O
Poirel
Eve
E
Lepicard
Salah El
SE
Mestikawy
Gérard
G
Hilaire
Jorge
J
Gallego
D026922:Amino Acid Transport Systems, Acidic / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000033:anatomy & histology / Q000502:physiology; D000860:Hypoxia / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D012119:Respiration; D012701:Serotonin / Q000502:physiology; D013312:Stress, Physiological
D026922:Amino Acid Transport Systems, Acidic; D012701:Serotonin; C504941:Slc17a8 protein, mouse