Region-Specific Expression of Brain-Derived Neurotrophic Factor (BDNF) mRNA after Long Term Treatment with Lithium Carbonate.

Abstract

There is much evidence that chronic administration of lithium ion protects neurons in vitro, and in various animal models of neurological diseases. The possibility has been raised that the neuroprotective effects of lithium ion may be mediated through regulation of brain-derived neurotrophic factor (BDNF). Recently, lithium ion has been shown to selectively protect spinal motor neurons in animal models of amyotrophic lateral sclerosis (ALS) by preventing the apoptosis component. In this study, investigation was undertaken to determine if lithium ion would regulate expression of BDNF for its anti-apoptosis action. RT-PCR and fluorescence in situ hybridization experiments were performed to determine the lithium-sensitive expression profile in brain and spinal cord. In the brain, chronic treatment with lithium increased mRNA expression of BDNF in the cerebral cortex, the hippocampal formation, the striatum, the diencephalons, and the midbrain, but not in the cerebellum. In particular, BDNF mRNA expression was exclusively increased in neurons. Long-term treatment with lithium increased levels of mRNA in all regions of the spinal cord including the cervical, thoracic, and lumbar regions. Immunohistochemistry and in situ hybridization revealed that BDNF expression was increased selectively in large spinal motor neurons of mice treated with lithium. The present findings suggest that chronic treatment with lithium increases expression of BDNF in various populations of neurons in the brain, which underlies the pharmacological action of lithium as a mood stabilizer, and also suggests a novel therapeutic potential as a neurotrophic agent. Dopaminergic neurons in the substantial nigra were shown to undergo degeneration in G93A transgenic mouse models of ALS. To examine if lithium ion would protect the dopaminergic neurons in ALS mice, loss of the dopaminergic neurons was first verified by counting cells immunoreactive to tyrosine hydroxylase (TH) antibody using a stereology method in 16-week old male G93A mice. There was a 28 % decrease in the number of dopaminergic neurons in the ALS mice. The degeneration of the dopaminergic neurons was prevented by daily administration of lithium in the diet for 4 weeks. In the G93A mice, expression of BDNF mRNA was significantly decreased compared to the wild type. In G93A mice treated with lithium ion, expression of BDNF mRNA was comparable to the control. Thus, lithium ion prevents degeneration of the dopaminergic neurons in G93A mice through mechanisms involving upregulation of BDNF.