Changes in the GABA-ergic system induced by trimethyltin application in the rat.
Ingestion of trimethyltin (TMT) produces mental confusion and temporal lobe seizures in humans. In rats, it causes increased seizure susceptibility, hyperactivity, aggression, learning impairment, and neuronal loss especially of hippocampal CA3c pyramidal cells and in the piriform cortex. As some of these symptoms may be due to impaired inhibitory neurotransmission, mRNA levels of the nine major GABA(A) receptor subunits, of GABA(B) receptors 1 and 2, and the 65- and 67-kD glutamate decarboxylase (GAD) variants were investigated by in situ hybridization 2, 5, and 16 days after TMT administration. GAD-65 mRNA levels were enhanced in hippocampal interneurons by up to 46% 5 days after TMT application, suggesting increased activity of respective neurons. In the granule cell layer, only the GABA(A) receptor subunit delta mRNA was altered (decreased by 48%). In the hippocampal sector CA3c and in the piriform cortex, mRNA levels of GABA(A) receptor subunits alpha1, alpha5, beta1, beta2, beta3, gamma2 and of both GABA(B) receptors declined (by 46-72%) after 5-16 days, being consistent with the extensive cell loss. In contrast, subunit alpha2 mRNA levels decreased already after 2 days at an extent exceeding the cell loss in CA3. Subunit alpha4 mRNA levels increased (about two-fold) in surviving CA3 neurons. In sector CA1, mRNA levels of subunits alpha1, alpha5, beta2, beta3, and gamma2 decreased by 35-54% in spite of only a minor (9%) cell loss. The data indicate neurodegeneration related decreases in mRNA levels in sector CA3 and piriform cortex, whereas decreases in sector CA1 may be a consequence of impaired excitatory input to this area.
Nishimura
T
T
Department of Pharmacology, University of Innsbruck, Peter-Mayr-Str. 1a, A-6020, Innsbruck, Austria. t.nishimura@aol.com
Schwarzer
C
C
Furtinger
S
S
Imai
H
H
Kato
N
N
Sperk
G
G
D000374:Aggression / Q000187:drug effects*; D000818:Animals; D016923:Cell Death; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D005968:Glutamate Decarboxylase / Q000096:biosynthesis* / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D006948:Hyperkinesis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology* / Q000633:toxicity; D021122:Protein Subunits; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000096:biosynthesis* / Q000235:genetics; D018080:Receptors, GABA-B / Q000096:biosynthesis / Q000235:genetics; D014298:Trimethyltin Compounds / Q000494:pharmacology* / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D021122:Protein Subunits; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D014298:Trimethyltin Compounds; C046488:trimethyltin; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase