Involvement of BDNF/ERK signaling in spontaneous recovery from trimethyltin-induced hippocampal neurotoxicity in mice

• Trimethyltin (TMT) increased ERK1/2 activation in the mouse hippocampus.
• BDNF/TrkB expression was similar to that of ERK1/2 activation after TMT treatment.
• ERK1/2 was mainly activated in immature progenitor neurons in TMT-treated hippocampal DGs.
• Exogenous BDNF alleviated TMT-induced in vitro toxicity via the ERK activation.
• BDNF/ERK signaling may play roles in spontaneous recovery from TMT-induced toxicity.

Trimethyltin (TMT) toxicity causes histopathological damage in the hippocampus and induces seizure behaviors in mice. The lesions and symptoms recover spontaneously over time; however, little is known about the precise mechanisms underlying this recovery from TMT toxicity. We investigated changes in the brain-derived neurotrophic factor/extracellular signal-regulated kinases (BDNF/ERK) signaling pathways in the mouse hippocampus following TMT toxicity. Mice (7 weeks old, C57BL/6) administered TMT (2.6 mg/kg intraperitoneally) showed acute and severe neurodegeneration with increased TUNEL-positive cells in the dentate gyrus (DG) of the hippocampus. The mRNA and protein levels of BDNF in the hippocampus were elevated by TMT treatment. Immunohistochemical analysis showed that TMT treatment markedly increased phosphorylated ERK1/2 expression in the mouse hippocampus 1–4 days after TMT treatment, although the intensity of ERK immunoreactivity in mossy fiber decreased at 1–8 days post-treatment. In addition, ERK-immunopositive cells were localized predominantly in doublecortin-positive immature progenitor neurons in the DG. In primary cultured immature hippocampal neurons (4 days in vitro), BDNF treatment alleviated TMT-induced neurotoxicity, via activation of the ERK signaling pathway. Thus, we suggest that BDNF/ERK signaling pathways may be associated with cell differentiation and survival of immature progenitor neurons, and will eventually lead to spontaneous recovery in TMT-induced hippocampal neurodegeneration.