Differential expression of glutamate receptor subtypes in human brainstem sites involved in perinatal hypoxia-ischemia

Abstract

This study delineates the development of N-methyl-D-aspartate (NMDA) and non-NMDA receptor binding in the human brainstem, particularly as it relates to issues of the trophic effects of glutamate, the glutamate-mediated ventilatory response to hypoxia, and regional excitotoxic vulnerability to perinatal hypoxia-ischemia. We used tissue autoradiography to map the development of binding to NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionate (AMPA), and kainate receptors in brainstem sites involved in the glutamate ventilatory response to hypoxia, as well as recognized sites vulnerable to perinatal hypoxia-ischemia. NMDA receptor/channel binding was virtually undetectable in all regions of the human fetal brainstem at midgestation, an unexpected finding given the trophic role for NMDA receptors in early central nervous system maturation in experimental animals. In contrast, non-NMDA (AMPA and kainate) receptor binding was markedly elevated in multiple nuclei at midgestation. Although NMDA binding increased between midgestation and early infancy to moderately high adult levels, AMPA binding dramatically fell over the same time period to low adult levels. High levels of kainate binding did not change significantly between midgestation and infancy, except for an elevation in the infant compared with fetal inferior olive; after infancy, kainate binding decreased to negligible adult levels. Our data further suggest a differential development of components of the NMDA receptor/channel complex. This baseline information is critical in considering glutaminergic mechanisms in human brainstem development, physiology, and pathology.

Modeling the Encephalopathy of Prematurity in Animals: The Important Role of Translational Research

“…Nevertheless, information is relatively limited about these factors in the human preterm brain. Transient expression of glutamate receptors has been described in the developing human basal ganglia [28] and brainstem [58, 59]. The expression levels and cellular localization of several antioxidant enzymes have also been defined in the basal ganglia and brainstem by immunohistochemistry [60].…”

Hypoxic-Ischemic Encephalopathy in the Term Infant

“…Autoradiographic studies in human postmortem tissue indicate that AMPA and/or kainate receptor binding is elevated in these vulnerable regions in the midgestation fetus and neonate59, 60 and then declines at later ages, while NMDA receptor binding is undetectable at midgestation and then matures in the postnatal period. Elevated levels of AMPA/kainate receptors in the griseum pontis at midgestation and early infancy may be relevant to pontosubicular necrosis from HI during the last trimester and early infancy 60.…”

“…Autoradiographic studies in human postmortem tissue indicate that AMPA and/or kainate receptor binding is elevated in these vulnerable regions in the midgestation fetus and neonate59, 60 and then declines at later ages, while NMDA receptor binding is undetectable at midgestation and then matures in the postnatal period. Elevated levels of AMPA/kainate receptors in the griseum pontis at midgestation and early infancy may be relevant to pontosubicular necrosis from HI during the last trimester and early infancy 60. AMPA receptors probably mediate the stimulus of breathing movements via the nucleus of the solitary tract during the fetal period, while NMDA receptors likely mediate stimulation of this nucleus in response to hypoxia and sustained ventilation in the newborn and infant,60 suggesting that the vulnerability of these brainstem structures to injury is related to the adaptive roles that the different types of glutamate receptors play in normal neuronal development and plasticity.…”

Neuroprotective effect of acid-sensing ion channel inhibitor psalmotoxin-1 after hypoxia–ischemia in newborn piglet striatum

“…MK-801 can cause reversible vacuolization in cortical neurons even in a dose of 0.1mg/kg (Allen and Iversen, 1990) and can trigger widespread apoptosis in the developing brain (Ikonomidou et al, 1999). In addition, NMDA receptors mediate brain stem activity in response to hypoxia and help sustain ventilation in the newborn (Panigrahy et al, 2000). In contrast to the effects in immature rodents, intravenous injection of 3 mg/kg MK-801 provides no neuroprotection and worsens neurologic outcomes in a piglet model of carotid artery ligation (LeBlanc et al, 1991).…”