Alterations in Serotonin Signalling Are Involved in the Hyperactivity of Pitx3-deficient Mice

Eur J Neurosci. 2008 Jan;27(2):388-95. doi: 10.1111/j.1460-9568.2008.06032.x.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Female
  • Homeodomain Proteins / genetics
  • Hyperkinesis / genetics
  • Hyperkinesis / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Protein Binding / physiology
  • Serotonin / genetics
  • Serotonin / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / genetics
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Signal Transduction / physiology*
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics

Substances

  • Homeodomain Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, mouse
  • Transcription Factors
  • homeobox protein PITX3
  • Serotonin