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In utero hypoxic ischemia decreases the cholinergic agonist-stimulated poly-phosphoinositide turnover in the
1Department of Child Health, University of Missouri, Columbia 65212, USA.
Insights
Perinatal hypoxic-ischemic (HI) insult impairs poly-phosphoinositide signaling in developing rat brains. This disruption affects brain development and may contribute to functional deficits.
Area of Science:
- Neuroscience
- Developmental Biology
- Biochemistry
Background:
- Perinatal hypoxic-ischemic (HI) insult disrupts brain development, causing functional and behavioral abnormalities.
- Poly-phosphoinositide (PI) signaling pathways are crucial for cellular processes during brain development.
Purpose of the Study:
- To investigate the impact of in utero HI insult on poly-PI turnover in the developing rat brain.
- To assess the effects of HI on cholinergic-stimulated PI signaling in cortical slices.
Main Methods:
- In utero HI insult was induced in near-term rat fetuses.
- Poly-PI signaling activity was measured in vivo using [3H]inositol and lithium.
- Cholinergic-stimulated PI turnover was examined in brain slices from HI-exposed pups.
Main Results:
- In control pups, lithium increased inositol phosphate (IP) levels more significantly in the cerebrum than the cerebellum.
- In utero HI insult caused a minor increase in cerebral IP but no change in cerebellar IP in vivo.
- HI exposure (10-15 min) significantly reduced carbachol-stimulated IP increase in cortical slices from 2-week-old pups.
Conclusions:
- In utero HI insult affects the cholinergic-stimulated poly-PI signaling pathway in the developing brain.
- This disruption in PI signaling may underlie functional deficits observed after perinatal HI.
- The study highlights the vulnerability of PI signaling to developmental insults.
Abstract:
Perinatal hypoxic-ischemic (HI) insult is known to cause cellular and molecular disturbances leading to functional and behavioral abnormalities during brain development. In this study, we examined the effects of an in utero HI insult on poly-phosphoinositide turnover in vivo in the cerebrum and cerebellum as well as cholinergic-stimulated turnover in cortical slices from developing rat brain. In utero HI treatment was carried out by clamping the uterine blood vessels of near-term fetuses for 5, 10 and 15 min followed by resuscitation of the newborn pups. The in vivo protocol for examining poly-PI signaling activity in 2 week-old pup brain involved intracerebral injection of [3H]inositol for 16 hr and subsequent intraperitoneal injection with lithium (8 meq/kg) for 4 hr prior to decapitation. In the control pups, lithium elicited a 2.6 fold increase in labeled inositol phosphate (IP) in the cerebrum as compared to a 1.3 fold increase in the cerebellum. In utero HI insult (5 to 15 min) resulted in a small increase in labeled IP in the cerebrum but not in the cerebellum. Carbachol stimulation of poly-PI turnover was examined in brain slices prelabeled with [3H]inositol in vivo. Incubation of the prelabeled slices with carbachol in the presence of LiCl (10 mM) resulted in a time-, dose- and age-dependent increase in labeled IP. Brain slices from 2 week-old pups that experienced in utero HI-treatment for 10 and 15 min (but not 5 min) showed a significant decrease in carbachol-stimulation of labeled IP as compared with control pups. These results indicate the effects of in utero HI on the choninergic-stimulated poly-PI signaling pathway and its implication on related functional deficits in the developing brain.