Dopamine inhibits mitochondrial motility in hippocampal neurons

Abstract

Background: The trafficking of mitochondrial within neurons is a highly regulated process. In an earlier study, we found that serotonin (5-HT), acting through the 5-HT1A receptor subtype, promotes axonal transport of mitochondrial in cultured hippocampal neurons by acting Akt activity, and consequently decreasing glycogen synthase kinase (GSK3β) activity. This finding suggests a critical role for neuromodulators in the regulation of mitochondrial trafficking in neurons, in the present study, we investigate the effects of a second important neuromodulator, dopamine, on mitochondrial transport in hippocampal neurons. Methodology/Principal Findings: Here, we show that dopamine, like 5-HT, regulates mitochondrial motility in cultured hippocampal neurons through the Akt-GSK3β signaling cascade. But, in contrast to the stimulatory effect of 5-HT, administrations of exogenous dopamine or bromocriptine, a dopamine 2 receptor (D2R) agonist, caused an inhibition of mitochondrial movement. Moreover, pretreatment with bromocriptine blocked the stimulatory effect of 5-HT on mitochondrial movement. Conversely, in cells pretreated with 5-HT, no further increases in movement were observed after administration of haloperidol, a D2R antagonist. In contrast to the effect of the D2R agonist, addition of SKF3893, a dopamine 1 receptor (D1R) agonist, promoted mitochondrial transport, indicating that the inhibitory effect of dopamine was actually the net summation of opposing influences of the two receptor subtypes. The most pronounced effect of dopamine signals was on mitochondrial that were already moving directionally. Western blot analysis revealed that treatment with either 2 D2R agonist or a D1R antagonist decreased Akt activity, and conversely, treatment with either a D2R antagonist or a D1R agonist increased Akt activity. Conclusions/Significance: Our observations strongly suggest a role for both dopamine and 5-HT in regulating mitochondrial movement, and indicate that the integrated effect of these two neuromodulators may be important in determining the distribution of energy sources in neurons. © 2008 Chen et al.