Effect of Prenatal Hypobaric Hypoxia on Glutamatergic Signal Transduction in Rat Brain

Abstract

Ca(2+)-mediated signal transduction of group I metabotropic glutamate receptors (ImGluR) was studied in the brain of young (15 days) and old rats (90 days) exposed to severe hypobaric hypoxia on gestation days 14-16. Changes in the concentration of bound intracellular Ca(2+) (Ca(2+) response) were evaluated after repeated application of a selective ImGluR agonist 3,5-dihydroxyphenylglycine (DHPG) to cultured brain slices. Primary application of DHPG for 2 min induced a negative Ca(2+) response in slices from 15-day-old intact animals, while repeated application caused a positive response. In slices from 90-day-old control animals, both responses were negative. In slices from rats of both age groups subjected to severe prenatal hypobaric hypoxia, both responses were mainly positive, but short-term negative components were present in adult animals. Our results suggest that severe hypobaric hypoxia changes the balance between the two constitutive signal pathways triggered by ImGluR (inosine triphosphate and diacylglycerol pathways). This procedure is followed by the increased influx of extracellular Ca(2+) (as compared to Ca(2+) release from the intracellular stores). This imbalance is particularly pronounced at the early stage of ontogeny.

Prenatal hypoxia modifies working memory and the activity of hippocampal polyphosphoinositide system in rats

“…Although at the early stages of brain development IP3R1 are few, they do play an important role because of the high sensitivity of the phosphoinositide system [24]. These data are well consistent with our previous results on Са 2+ signaling in juvenile and adult animals [12].…”

“…The heightened expression of IP3R1 leads to an increase in Са 2+ release from intracellular stores and activation of the Са 2+ -dependent processes such as apoptosis, intracellular рН regulation and triggering gene expression [25,26]. The data on the upregulation of IP3R1 expression by prenatal hypoxia obtained herein are consistent with our previous studies on the effect of prenatal hypoxia on the functional state of the Ca 2+ -regulatory system in rats of the same age groups through the evaluation of Са 2+ -signaling mediated by the excitation of group I metabotropic glutamate receptors (ImGluR) in surviving brain slices [12].…”

“…Activation of the polyphosphoinositide (PPI) signaling system, which leads to Са 2+ release from the intracellular calcium stores [8][9][10], plays an important role in regulation of cell survival and death via apoptosis [11]. In our previous studies we discovered the significant changes in neocortical metabolism of polyphosphoinositides and their ability to respond to the effect of glutamate in rats that exposed to hypobaric hypoxia at different stages of their prenatal development [12]. Considering the learning disability that we and other researchers observed, it is important to investigate the status of the PPI system in the hippocampus of rats exposed to prenatal hypoxia.…”

New Aspects of Central Nervous System Adaptation to Prenatal Hypoxia

“…In some especially sensitive brain structures, for example, in cerebral cortex, the normal balance of neuromediators (glutamate, dopamine, serotonin, acetylcholine, etc.) and products of their metabolism changes under hypoxic action [7], besides, structural and functional impairments of cell membrane properties take place causing cells to die [8]. Hypoxia is also able to change the transcription activity of genes responsible for programmed cell death [9].…”

“…However, currently developed experimental models are not accurate enough since they often do not make it possible to achieve pronounced hypoxic injury of the fetus brain and to examine the effect of chronic hypoxic prenatal stress. The overwhelming majority of authors offer different variants of a single hypoxic impact on a pregnant mouse [5,7,10,11]. As the adaptation potential in experimental animals is higher than in a human, such approaches do not allow the researchers to achieve marked impairments of the CNS function.…”