NMDA Receptor Modification during Graded Hypoxia in the Cerebral Cortex of Newborn Piglets

Fritz, Karen I; Zubrow, Alan B.; Mishra, Om P.; Delivoria‐Papadopoulos, Maria

doi:10.1159/000064152

Cited by 11 publications

(8 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Glycine content is elevated in plasma of depressed patients [49]. Although glycine also serves as a co-agonist for glutamate coupling with excitatory NMDA receptors [69], under hypoxia the activation of the receptors by glutamate is increased, and the activation by glycine is decreased [70]. Brain glycine content was significantly increased after hypoxia exposure in mice [71], as well as observed in our study.…”

Section: Discussionsupporting

confidence: 82%

Neurochemical alterations in frontal cortex of the rat after one week of hypobaric hypoxia

Bogdanova

Abdullah

Kanekar

et al. 2014

Behavioural Brain Research

View full text Add to dashboard Cite

Residing at high altitude may lead to reduced blood oxygen saturation in the brain and altered metabolism in frontal cortical brain areas, probably due to chronic hypobaric hypoxia. These changes may underlie the increased rates of depression and suicidal behavior that have been associated with life at higher altitudes. To test the hypothesis that hypobaric hypoxia is responsible for development of mood disorders due to alterations in neurochemistry, we assessed depression-like behavior in parallel to levels of brain metabolites in rats housed at simulated altitude. 32 female Sprague Dawley rats were housed either in a hypobaric hypoxia chamber at 10,000 ft of simulated altitude for 1 week or at local conditions (4500 ft of elevation in Salt Lake City, Utah). Depression-like behavior was assessed using the forced swim test (FST) and levels of neurometabolites were estimated by in vivo proton magnetic resonance spectroscopy in the frontal cortex, the striatum and the hippocampus at baseline and after a week of exposure to hypobaric hypoxia. After hypoxia exposure the animals demonstrated increased immobility behavior and shortened latency to immobility in the FST. Elevated ratios of myo-inositol, glutamate, and the sum of myo-inositol and glycine to total creatine were observed in the frontal cortex of hypoxia treated rats. A decrease in the ratio of alanine to total creatine was also noted. This study shows that hypoxia induced alterations in frontal lobe brain metabolites, aggravated depression-like behavior and might be a factor in increased rates of psychiatric disorders observed in populations living at high altitudes.

show abstract

Section: Discussionsupporting

confidence: 82%

Neurochemical alterations in frontal cortex of the rat after one week of hypobaric hypoxia

Bogdanova

Abdullah

Kanekar

et al. 2014

Behavioural Brain Research

View full text Add to dashboard Cite

show abstract

“…Decreased phosphorylation is consistent with decreased NMDAR function. Decreased phosphorylation of NMDAR in turtle brain, newborn piglet brain, and 1‐ or 3‐week‐old rats is thought to contribute to anoxia and hypoxia/ischemia tolerance via maintenance of critical [Ca 2+ ] i (Bickler,1998; Fritz et al, 2002; Vij et al,2005). Therefore, down‐regulation of NMDAR via decreased phosphorylation could be a common mechanism adopted by hypoxia/ischemia‐tolerant animals.…”

Section: Discussionmentioning

confidence: 99%

“…N‐methyl‐D‐aspartate receptors (NMDAR) play a key role in excitotoxicity and synaptic plasticity (Ascher and Nowak,1986; Choi,1995). Down‐regulation of NMDAR has been shown to contribute to hypoxia and ischemia tolerance in developing brains of rats and piglets (Mishra et al,2001; Fritz et al,2002) and to long‐term anoxia tolerance in brains of Western painted turtles ( Chrysemys picta ; Bickler,1998). The objective of this study was, therefore, to test the hypothesis that NMDAR function is down‐regulated in hibernating AGS.…”

mentioning

confidence: 99%

Decreased NR1 phosphorylation and decreased NMDAR function in hibernating Arctic ground squirrels

et al. 2006

View full text Add to dashboard Cite

Heterothermic mammals such as ground squirrels tolerate ischemia and N-methyl-D-aspartate (NMDA) better than homeothermic mammals such as rats both in vivo and in vitro, and this tolerance is enhanced in the hibernating state. However, the cellular mechanisms underlying this tolerance remain unclear. NMDA receptors (NMDAR) play a key role in excitotoxicity. The purpose of the current study was therefore to test the hypothesis that NMDAR are down-regulated in hibernating Arctic ground squirrels (hAGS; Spermophilus parryii). To address this hypothesis, we used Western blot analysis to investigate NMDAR phosphorylation, an activator of NMDAR function, and internalization in naïve hippocampal tissue from hAGS, interbout euthermic AGS (ibeAGS), and rats. Furthermore, we used fura-2 calcium imaging to examine NMDAR function in cultured hippocampal slices from hAGS, ibeAGS, and rats. We report that phosphorylation of the NMDAR1 (NR1) subunit is decreased in hippocampal tissue from hAGS and that the NMDAR component of Glu-induced increase in [Ca 2+ ] i is decreased in hippocampal slices from hAGS. Moreover, the fraction of NR1 in the functional membrane pool in AGS is less than that in rats. Keywordshibernation; hippocampal slices; excitotoxicity; stroke; fura-2 Stroke is a primary cause of disability in the United States, and studies in traditional laboratory animals such as rats have produced a poor yield of pharmacotherapies (Sareen, 2002). Heterothermic mammals (e.g., ground squirrels) tolerate experimental hypoxia and ischemia significantly better than homeothermic mammals (e.g., rats) both in vivo and in vitro (Frerichs et al., 1998;Drew et al., 2004; Dave et al., 2006;Ross et al., 2006). Tolerance to central nervous system injury is enhanced in the hibernating state (Frerichs et al., 1998;Zhou et al., 2001;Ross et al., 2006). In addition, arousal from hibernation enhances learning in ground squirrels (Mihailovic et al., 1968;Weltzin et al., 2006). Nmethyl-D-aspartate receptors (NMDAR) play a key role in excitotoxicity and synaptic plasticity (Ascher and Nowak, 1986;Choi, 1995). Down-regulation of NMDAR has been shown to contribute to hypoxia and ischemia tolerance in developing brains of rats and piglets (Mishra et al., 2001;Fritz et al., 2002) Western painted turtles (Chrysemys picta;Bickler, 1998). The objective of this study was, therefore, to test the hypothesis that NMDAR function is down-regulated in hibernating AGS.Functional NMDAR are heteromeric and formed by NMDAR1 (NR1) subunits in various combinations with NMDAR2A-D (NR2A-D) subunits (Carroll and Zukin, 2002). NR1 is required to form functional NMDAR, whereas NR2 subunits play regulatory roles. Phosphorylation of NR1 and NR2 subunits enhances receptor function (Liu and Zhang, 2000). Internalization or altered insertion in the plasma membrane can also alter NMDAR function (Ehlers, 2000;Carroll and Zukin, 2002). To test the hypothesis that NMDAR function is down-regulated in hibernation, we first used Western blotting analysis to investigate N...

show abstract

“…Postnatal hypoxia increases NMDA receptor affinity for the antagonist MK-801 in the piglet cortex [2], but decreases it in several brain regions of the infant rat, including the hypothalamus, amygdaloid nuclei, entorhinal cortex, perirhinal cortex and hippocampus [3]. Postnatal hypoxia also induced an increased affinity for glutamate [2], Mg 2+ [94,95], and for the antagonist, CPP (3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) [96,97], and reduced the numbers of glutamate [96,98] and CPP-binding sites [96,97]. Subunit-specific increases in nitration of the NR1, NR2A and NR2B have also been reported [99].…”

Section: Hypoxiamentioning

confidence: 99%

NMDA Receptors in the Developing Brain and Effects of Noxious Insults

Waters¹,

Machaalani²

2004

Neurosignals

View full text Add to dashboard Cite

This review covers normal expression of the NMDA receptor in the fetus and newborn, and then the response of the NMDA receptors within the central nervous system (CNS) during early development, to noxious stimuli. In the research setting, hypoxia is a commonly studied noxious stimulus that has been studied in a variety of contexts, including isolated hypoxia, or hypoxia combined with ischemia or hypercapnia, and delivered in single or repeated doses (intermittent stimuli). We review differences and commonalities between these experimental paradigms, and the sequelae of a common outcome, which is cell death, possibly through excitotoxic mechanisms. Finally, based on current literature, we will examine potential directions for clinical therapeutic interventions. By highlighting knowledge gaps in this field, we hope to encourage future research focusing on clinically relevant problems and outcomes in this area.

show abstract

NMDA Receptor Modification during Graded Hypoxia in the Cerebral Cortex of Newborn Piglets

Cited by 11 publications

References 31 publications

Neurochemical alterations in frontal cortex of the rat after one week of hypobaric hypoxia

Neurochemical alterations in frontal cortex of the rat after one week of hypobaric hypoxia

Decreased NR1 phosphorylation and decreased NMDAR function in hibernating Arctic ground squirrels

NMDA Receptors in the Developing Brain and Effects of Noxious Insults

Contact Info

Product

Resources

About