Abstract
Lithium, a mood stabilizer, is known to ameliorate the stress-induced decrease in hippocampal neurogenesis seen in animal models of stress-related disorders. However, it is unclear whether lithium has beneficial effect on neuronal repair following neuronal damage in neuronal degenerative diseases. Here, we evaluated the effect of in vivo treatment with lithium on the hippocampal neuronal repair in a mouse model of trimethyltin (TMT)-induced neuronal loss/self-repair in the hippocampal dentate gyrus (such mice referred to as “impaired animals”) [Ogita et al. (2005) J Neurosci Res 82: 609–621]. The impaired animals had a dramatically increased number of 5-bromo-2′-deoxyuridine (BrdU)-incorporating cells in their dentate gyrus at the initial time window (days 3 to 5 post-TMT treatment) of the self-repair stage. A single treatment with lithium produced no significant change in the number of BrdU-incorporating cells in the dentate granule cell layer and subgranular zone on day 3 post-TMT treatment. On day 5 post-TMT treatment, however, BrdU-incorporating cells were significantly increased in number by lithium treatment for 3 days. Most interestingly, chronic treatment (15 days) with lithium increased the number of BrdU-incorporating cells positive for NeuN or doublecortin in the dentate granule cell layer of the impaired animals, but not in that of naïve animals. The results of a forced swimming test revealed that the chronic treatment with lithium improved the depression-like behavior seen in the impaired animals. Taken together, our data suggest that lithium had a beneficial effect on neuronal repair following neuronal loss in the dentate gyrus through promoted proliferation and survival/neuronal differentiation of neural stem/progenitor cells in the subgranular zone.
Highlights
The concept that the adult mammalian brain contains populations of endogenous neural stem/progenitor cells (NPCs) has been widely accepted [1,2]
Even under normal physiological conditions in the adult, NSCs predominantly produce neurons including interneurons in the olfactory bulb in the case of NPCs derived from the subventricular zone and neuronal cells in the dentate gyrus in the case of NPCs derived from the subgranular zone (SGZ)
Following the TMT-induced neuronal loss in the dentate gyrus, a marked increase in the number of BrdUincorporating cells and of cells positive for nestin, NeuroD or DCX, which are neurogenesis-related markers, is seen in the dentate gyrus. Using this model of neuronal loss/self-repair in the dentate gyrus, we assessed the effect of lithium on neuronal regeneration following this neuronal loss
Summary
The concept that the adult mammalian brain contains populations of endogenous neural stem/progenitor cells (NPCs) has been widely accepted [1,2]. Even under normal physiological conditions in the adult, NSCs predominantly produce neurons including interneurons in the olfactory bulb in the case of NPCs derived from the subventricular zone and neuronal cells in the dentate gyrus in the case of NPCs derived from the SGZ. These NPCs have the ability to respond to brain damage by producing neural cells including neurons, astrocytes, and oligodendrocytes [5]. Through enhancement of neural repair processes, i.e., proliferation, migration, differentiation, and survival, NPCs have the ability to replace cells damaged/ lost following neural injury with new neuronal and glial cells. Treatment that enhances the neuronal repair process has been speculated to be a beneficial therapy for neuronal injury or neurodegenerative disorders
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