Lithium treatment in ovo: effects on embryonic heart rate, natural death of ciliary ganglion neurons, and brain expression of a highly conserved chicken homolog of human MTG8/ETO

Understanding the action of the mood stabilizer lithium is dependent on ava ilability of experimental models where lithium treatment at clinically rele vant concentrations induces marked phenotypic and genotypic changes. Here w e report on such changes in the chicken embryo. Lithium chloride (0.6 mM), applied in ovo 60 h after incubation, markedly delayed the heart rate incre ase observed from ED2.5 to ED5, and induced the brain expression of a new c hicken gene cETO from ED7 to ED15. At the same time the overall development al dynamics and embryo survival, or the expression of chicken gephyrin were not significantly affected. Furthermore, lithium treatment (0.3 mM, 48 h a fter incubation) abolished the difference in neuronal number between ED12 c iliary ganglia developing in the presence or absence of postganglionic targ et muscles. We show that cETO is a close homologue of the human transcripti on factor MTG8/ETO; named after its location on chromosome 8, and participa tion in chromosomal translocation 8;21 in myeloid leukemia. The mRNA and pr otein levels of ETO and gephyrin had a parallel course in chicken brain dev elopment suggesting that the expression of both genes is regulated mainly a t the level of gene transcription. However, the patterns of expression were markedly different. ETO peaked at ED7 and decreased five-fold at ED15. In contrast, gephyrin levels increased five-fold from ED7 to ED15. We propose that the induction of ETO expression, in concert with lithium-induced upreg ulation of other genes, such as PEBP2 beta and bcl-2, is participating in t he neuroprotective effect of chronic lithium treatment. (C) 2000 Elsevier S cience B.V. All rights reserved.