The effects of acute and long-term lithium treatments on trkB neurotrophin receptor activation in the mouse hippocampus and anterior cingulate cortex
Introduction
Brain-derived neurotrophic factor (BDNF), a member of the NGF family of neurotrophic factors, regulates the differentiation and survival of specific neuronal populations in the brain (Huang and Reichardt, 2001). In addition, BDNF is importantly involved in activity-dependent plastic changes in neuronal connectivity, thus suggesting that BDNF acts as a short and long-term modulator of the activity and maintenance of neuronal circuits (Poo, 2001, Lu, 2003, Thoenen, 1995).
The synaptic actions of BDNF are mediated through trkB receptor tyrosine kinases which upon ligand binding dimerize and become autophosphorylated in their intracellular catalytic domain (Y705/6) (Huang and Reichardt, 2001). This phosphorylation event induces the autophosphorylation of tyrosines 515 and 816. In short, Y515 mediates the activation of signaling cascades that lead to enhanced neuronal survival and differentiation, whereas Y816 mediates the activation of phospholipase-Cγ thus leading to the alterations in intracellular Ca2+ and the activation of protein kinase C (Huang and Reichardt, 2001).
Recent evidence suggests that insufficient neurotrophin function is a key factor in the etiology of mood disorders: neuropathological and neuroimaging studies of bipolar and depressive patients have demonstrated that these disorders are frequently associated with atrophic changes in neuronal and/or glial cells, particularly in the hippocampus and anterior cingulate cortex (reviewed by Beyer and Krishnan, 2002, Campbell and MacQueen, 2004, Drevets, 2000, Manji et al., 2001). Moreover, the hippocampal expression of BDNF is down-regulated by stress which is thought to precipitate affective disorders in some individuals (Smith et al., 1995, Rasmusson et al., 2002). Furthermore, the val66met polymorphism of the human BDNF gene, which results in reduced neuronal trafficking and release of BDNF (Chen et al., 2004), has been associated with familial bipolar disorder (Sklar et al., 2002, Neves-Pereira et al., 2002).
Although lithium has been employed in the treatment of bipolar disorder for over 50 years, its exact mechanism of action remains ambiguous. Nevertheless, it has emerged that lithium, like antidepressants, enhance BDNF-mediated trkB signaling in the brain, particularly in the hippocampus and anterior cingulate cortex (Hashimoto et al., 2004, Castren, 2004). For example, many studies have reported that long-term lithium treatment enhanced or modulated BDNF gene expression predominantly in these brain areas (Einat et al., 2003, Jacobsen and Mork, 2004, Fukumoto et al., 2001, Hashimoto et al., 2002, Angelucci et al., 2003). In addition, lithium increases neurogenesis, a form of plasticity, in rodent hippocampus (Chen et al., 2000). Also, at least some of structural alterations seen in the brains of bipolar patients are reversed by lithium (Drevets, 2000, Moore et al., 2000).
Although lithium has been shown to induce some of the signaling cascades downstream of trkB in the rodent hippocampus and frontal cortex (Einat et al., 2003, Mai et al., 2002, Nemeth et al., 2002) and the autophosphorylation of trkB in primary cortical cultures (Hashimoto et al., 2002), direct evidence that lithium indeed activates trkB in vivo is lacking. Our previous findings that acute and long-term treatments with antidepressant drugs induce trkB autophosphorylation specifically in hippocampus and anterior cingulate cortex in vivo (Saarelainen et al., 2003) prompted us to study the effects of lithium in a similar manner.
Section snippets
Animal care
Adult male Balb/C mice were employed in all experiments. This mouse strain is particularly relevant in experiments addressing the effects of mood-altering drugs since they are highly emotional and responsive to the behavioural effects of antidepressants (Ducottet et al., 2003, Dulawa et al., 2004, Englander et al., 2005). Moreover, this mouse strain demonstrates increased trkB autophosphorylation in response to acute treatment with the antidepressant imipramine (Fig. 1B). All experiments were
Animal weights and lithium measurements
LiCl treatments did not produce symptoms characteristic of lithium intoxication (Timmer and Sands, 1999). Furthermore, long-term treatment with LiCl did not affect weight gain (data not shown). Thirty minutes following acute administration of LiCl (50 and 100 mg/kg), plasma Li+ levels were increased to 0.46 ± 0.04 mEq/L and 1.10 ± 0.19 mEq/L, respectively. These plasma Li+ contents are considered to be below to the toxic concentrations of Li+ in humans (Timmer and Sands, 1999). Moreover, 24 h after the
Discussion
The present study examined the effects of acute and long-term treatment with lithium on trkB receptor activation and signaling in vivo. In a manner similar to that observed with acute antidepressant treatments (Saarelainen et al., 2003), acute administration of LiCl produced a significant activation of trkB receptors within 30 min in the mouse anterior cingulate cortex (AC). Activation of trkB receptors in the hippocampus (HC) was not altered by acute treatment with LiCl. Interestingly, however,
Acknowledgments
The authors would like to thank L. Kaskela, O. Nikkilä and several other members of Neuroscience Center for excellent technical assistance, S. Pietiläinen for animal care and O. O'Leary for excellent comments about the manuscript. T.R. is a recipient of the Finnish Graduate School for Neurosciences studentship. This study was supported by the Sigrid Juselius Foundation, Sohlberg Foundation and the Academy of Finland.
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