S.M.S. and C.W.N. contributed equally to this work.
Alterations in serotonin signalling are involved in the hyperactivity of Pitx3-deficient mice
Article first published online: 18 JAN 2008
European Journal of Neuroscience
Volume 27, Issue 2, pages 388–395, January 2008
How to Cite
Smits, S. M., Noorlander, C. W., Kas, M. J. H., Ramakers, G. M. J. and Smidt, M. P. (2008), Alterations in serotonin signalling are involved in the hyperactivity of Pitx3-deficient mice. European Journal of Neuroscience, 27: 388–395. doi: 10.1111/j.1460-9568.2008.06032.x
- Issue published online: 18 JAN 2008
- Article first published online: 18 JAN 2008
- Received 11 July 2007, revised 30 November 2007, accepted 4 December 2007
- dl-p-chlorophenylalanine methyl ester hydrochloride;
- Pitx3 deficiency;
Pitx3 deficiency in mice causes a dramatic loss of dopaminergic neurones located in the substantia nigra pars compacta during development. This early disruption of the nigrostriatal pathway in Pitx3-deficient mice is characterized by increased spontaneous home-cage activity levels during the habitual sleep phase of these animals. These findings are reminiscent of the spontaneous hyperactivity in mice neonatally lesioned with 6-hydroxydopamine, which is caused by an extensive serotonergic hyperinnervation of the striatum. The present study investigated whether an imbalance between dopamine (DA) and serotonin (5-HT) signalling is involved in the behavioural phenotype of Pitx3-deficient mice. Serotonergic hyperinnervation was demonstrated by increased [3H]-citalopram autoradiographic binding specifically in the dorsal striatum of adult Pitx3-deficient mice, indicating alterations in 5-HT transporter levels that correlated to DA dysfunction in Pitx3 deficiency. In addition, stimulus-induced release of DA and 5-HT indicated an altered balance between these neurotransmitters in the dorsal striatum of Pitx3–/– mice. To determine whether the increased 5-HT signalling was involved in the spontaneous hyperactivity during the light phase observed in Pitx3 deficiency, we treated Pitx3-deficient and control mice with the selective irreversible tryptophan hydroxylase inhibitor p-chlorophenylalanine to decrease 5-HT levels. Reduction of 5-HT levels in Pitx3-deficient mice decreased their locomotor activity to normal levels, whereas the same treatment increased the locomotor activity levels of control mice. Taken together, our results indicate alterations in 5-HT signalling in Pitx3-deficient mice that underlie their spontaneous hyperactivity.