Low-concentration tributyltin perturbs inhibitory synaptogenesis and induces neuronal death in immature but not mature neurons.
Tributyltin (TBT) has harmful effects on invertebrates. Reports indicate that intoxication of humans with organotin compounds could be associated with neurological symptoms such as epilepsy and amnesia; however, the toxicity mechanisms in mammals are unknown. TBT acts as a Cl(-)/OH(-) antiporter, and likely affects the GABAergic system by disturbing Cl(-) homeostasis. This study aimed to elucidate neurotoxic actions of TBT on mouse neocortical neurons during development. From 4 days in vitro (4 DIV) or 14 DIV in culture, cortical neurons were exposed to TBT continuously for 3 days. TBT-induced neuronal death at 30nM during DIV 4-6, and at 50nM during DIV 14-16. To further characterize this age-dependent cytotoxicity, miniature postsynaptic currents (mPSCs) were analyzed by whole-cell patch-clamp. The frequency of mPSCs was significantly reduced by treatment with 30nM TBT during DIV 4-6, but not DIV 14-16. After TBT treatment during DIV 4-6, GABA(A) receptor-mediated reversal potentials (E(GABA)) were significantly shifted negatively. The TBT-induced E(GABA) shift and neuronal death were reversed by increment of extracellular Cl(-) concentration, suggesting that disruption of Cl(-) homeostasis underlies the disturbance of neuronal ontogeny induced by TBT. These data indicate that the TBT may affect synaptogenesis and neuronal survival, particularly in early development.
Yamada
Junko
J
Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan. jyamada@cc.hirosaki-u.ac.jp
Inoue
Koichi
K
Furukawa
Tomonori
T
Fukuda
Atsuo
A
D000818:Animals; D017920:Antiporters / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena; D047108:Embryonic Development / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D005865:Gestational Age; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000378:metabolism; D055366:Synaptic Potentials / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*; D014220:Trialkyltin Compounds / Q000633:toxicity*
D017920:Antiporters; D002712:Chlorides; D004785:Environmental Pollutants; D011963:Receptors, GABA-A; D014220:Trialkyltin Compounds; C093920:chloride-base exchanger; C011559:tributyltin