[Genetic models to understand how serotonin acts during development]

Molecular genetics in mice have allowed significant progresses to be made in our understanding of the development of serotoninergic neurones and of their developmental role. The serotoninergic phenotype is determined by a sequence of transcription factors. Pet-1 is selectively expressed in the raphe and controls directly the transcription of the genes, encoding the biosynthetic enzyme of 5-HT, tryptophan hydroxylase (TPH), and the serotonin plasma membrane transporter (SERT). Expression of SERT can however occur independently of TPH during development and allows subpopulations of glutamatergic neurons to take up and to store 5-HT into synaptic vesicles via the vesicular monoamine transporter (VMAT). This could allow a tight homeostasis of 5-HT receptor activation on thalamic and retinal afferents. Mice with an excess or a severe reduction of 5-HT during development, such as the MAOA and the VMAT2 KO mice, show abnormalities that concern late stages of development: alterations in axon branching, dendritic remodeling and developmental cell death. Each of these effects could be mediated by a different 5-HT receptor. Abnormalities have been best characterized in the somatosensory and visual system but are likely to occur throughout the central nervous system.