Dysregulation of intracellular calcium homeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration induced by trimethyltin

Trimethyltin (TMT) intoxication is considered a suitable experimental model to study the molecular basis of selective hippocampal neurodegeneration as that occurring in several neurodegenerative diseases. We have previously shown that rat hippocampal neurons expressing the Ca²⁺-binding protein calretinin (CR) are spared by the neurotoxic action of TMT hypothetically owing to their ability to buffer intracellular Ca²⁺ overload. The present study was aimed at determining whether intracellular Ca²⁺ homeostasis dysregulation is involved in the TMT-induced neurodegeneration and if intracellular Ca²⁺-buffering mechanisms may exert a protective action in this experimental model of neurodegeneration. In cultured rat hippocampal neurons, TMT produced time- and concentration-dependent [Ca²⁺]i increases that were primarily due to Ca²⁺ release from intracellular stores although Ca²⁺ entry through Cav1 channels also contributed to [Ca²⁺]i increases in the early phase of TMT action. Cell pre-treatment with the Ca²⁺ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (2 μM) significantly reduced the TMT-induced neuronal death. Moreover, CR⁺ neurons responded to TMT with smaller [Ca²⁺]i increases. Collectively, these data suggest that the neurotoxic action of TMT is mediated by Ca²⁺ homeostasis dysregulation, and the resistance of hippocampal neurons to TMT (including CR⁺ neurons) is not homogeneous among different neuron populations and is related to their ability to buffer intracellular Ca²⁺ overload.