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Changes in the GABA-ergic system induced by trimethyltin application in the rat
T Nishimura1, C Schwarzer, S Furtinger
1Department of Pharmacology, University of Innsbruck, Peter-Mayr-Str. 1a, A-6020, Innsbruck, Austria. t.nishimura@aol.com
Brain Research. Molecular Brain Research
|December 18, 2001
Summary
Trimethyltin (TMT) exposure causes seizures and learning deficits by altering GABA(A) and GABA(B) receptor subunit mRNA levels in rat brains. Neurodegeneration in the hippocampus and piriform cortex correlates with reduced receptor expression, impacting inhibitory neurotransmission.
Area of Science:
- Neuroscience
- Neurotoxicology
- Molecular Biology
Background:
- Trimethyltin (TMT) is a neurotoxin causing seizures and cognitive impairment in humans and animals.
- TMT-induced neurotoxicity involves neuronal loss, particularly in the hippocampus and piriform cortex.
- These neurological deficits may stem from disruptions in inhibitory neurotransmission mediated by GABA receptors.
Purpose of the Study:
- To investigate the impact of TMT on the expression of GABA(A) and GABA(B) receptor subunits and glutamate decarboxylase (GAD) mRNA.
- To correlate changes in neurotransmitter receptor mRNA levels with neurodegeneration and functional deficits following TMT exposure.
Main Methods:
- In situ hybridization was used to quantify mRNA levels of nine major GABA(A) receptor subunits, GABA(B) receptors 1 and 2, and GAD variants.
- TMT was administered to rats, and tissue samples were analyzed at 2, 5, and 16 days post-exposure.
- Changes in mRNA levels were assessed in specific brain regions, including the hippocampus (CA1, CA3c) and piriform cortex.
Main Results:
- GAD-65 mRNA levels increased in hippocampal interneurons, suggesting heightened neuronal activity.
- Significant decreases in mRNA levels for multiple GABA(A) and GABA(B) receptor subunits were observed in hippocampal sector CA3c and piriform cortex, correlating with cell loss.
- In contrast, GABA(A) receptor subunit alpha4 mRNA increased in surviving CA3 neurons, while subunit alpha2 mRNA decreased rapidly in CA3.
- Sector CA1 showed decreased mRNA levels for several GABA(A) subunits despite minimal cell loss, indicating potential disruption of excitatory input.
Conclusions:
- TMT exposure induces region-specific alterations in GABAergic system gene expression.
- Decreased receptor subunit mRNA in CA3 and piriform cortex is linked to TMT-induced neurodegeneration.
- Altered receptor expression in CA1 may result from impaired excitatory input, contributing to TMT's neurotoxic effects.