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Excitotoxic brain injury suppresses striatal high-affinity glutamate uptake in perinatal rats
B Hu1, J W McDonald, M V Johnston
1Department of Pediatrics, University of Michigan, Ann Arbor 48109-0570.
Insights
N-methyl-D-aspartate (NMDA) neurotoxicity in immature rats significantly impairs high-affinity glutamate uptake (HAGU) in the striatum. This uptake reduction is dose-dependent and biphasic, showing early transient and later sustained loss post-injury.
Area of Science:
- Neuroscience
- Neurotoxicology
- Neurochemistry
Background:
- Immature rodent brain is vulnerable to glutamate excitotoxicity.
- N-methyl-D-aspartate (NMDA) is a potent neurotoxin in developing brains.
- NMDA receptor overactivation can lead to neuronal damage.
Purpose of the Study:
- To investigate the impact of NMDA-induced neurotoxicity on high-affinity glutamate uptake (HAGU) in the striatum of immature rats.
- To characterize the dose-response and temporal profile of HAGU alterations following NMDA lesioning.
Main Methods:
- Intrastriatal injection of NMDA in postnatal day 7 rats.
- Preparation of synaptosomes from lesioned and contralateral striata, as well as unlesioned controls.
- Assay of high-affinity [3H]glutamate uptake (HAGU) in synaptosomes.
Main Results:
- NMDA injection (25 nmol) caused a significant 44% decline in striatal HAGU 24 hours post-lesion.
- HAGU suppression was dose-dependent, with increasing NMDA doses leading to greater uptake reduction.
- A biphasic pattern of HAGU alteration was observed: an early transient suppression followed by a sustained loss at later time points (up to 5 days).
Conclusions:
- NMDA-induced neurotoxicity in immature rat striatum leads to significant and lasting impairments in high-affinity glutamate uptake.
- These findings highlight the disruption of glutamatergic neurotransmission following excitotoxic injury in the developing brain.
- The study provides insights into the neurochemical consequences of NMDA excitotoxicity relevant to developmental neurological disorders.
Abstract:
In immature rodent brain, the glutamate receptor agonist N-methyl-D-aspartate (NMDA) is a potent neurotoxin. In postnatal day (PND)-7 rats, intrastriatal injection of 25 nmol of NMDA results in extensive ipsilateral forebrain injury. In this study, we examined alterations in high-affinity [3H]glutamate uptake (HAGU) in NMDA-lesioned striatum. HAGU was assayed in synaptosomes, prepared from lesioned striatum, the corresponding contralateral striatum, or unlesioned controls. Twenty-four hours after NMDA injection (25 nmol), HAGU declined 44 +/- 8% in lesioned tissue, compared with the contralateral striatum (mean +/- SEM, n = 6 assays, p less than 0.006, paired t test). Doses of 5-25 nmol of NMDA resulted in increasing suppression of HAGU (5 nmol, n = 3; 12.5 nmol, n = 3; and 25 nmol, n = 5 assays; p less than 0.01, regression analysis). The temporal evolution of HAGU suppression was biphasic. There was an early transient suppression of HAGU (-28 +/- 4% at 1 h; p less than 0.03, analysis of variance, comparing changes at 0.5, 1, 2, and 3 h after lesioning); 1 or 5 days postinjury there was sustained loss of HAGU (at 5 days, -56 +/- 11%, n = 3, p less than 0.03, paired t test, lesioned versus contralateral striata).(ABSTRACT TRUNCATED AT 250 WORDS)