Mécanismes cellulaires et moléculaires régulés par SLITRK2 et SLITRK5 dans la formation des circuits dopaminergiques du mésencéphale
|Abstract:||Mesodiencephalic dopaminergic (mDA) neurons regulate key functions of the mammalian central nervous system, including voluntary movement, affection, reward, attention, working memory and learning. The specification of mDA neurons and dopaminergic circuitry’s establishment are finely regulated during development and require specific and complex spatial and temporal activation of transcription factors and target genes. The degeneration of mDA pathways or their dysfunction can lead to severe neurodegenerative or neuropsychiatric disorders, including Parkinson’s disease (PD), schizophrenia (SCZ) and obsessive-compulsive disorder (OCD). Lmx1a and Lmx1b transcription factors are early determinants of the dopaminergic fate, essential to mDA neurons differentiation and specification. Polymorphisms of LMX1A/B were previously linked to SCZ and OCD. Within the transcriptional targets of Lmx1a/b, we identified to members of the Slit and Trk (Slitrk) family, Slitrk2 and Slitrk5, controlling excitatory and inhibitory afferent synapses formation of mDA neurons. Mutations of SLITRK2 and SLITRK5 were also previously linked to various neuropsychiatric diseases. We here present the role of Lmx1a/b in the regulation of the electrophysiological activity of mDA neurons, by their transcriptional regulation of Slitrk2 and Slitrk5. Using a mDA neurons’ primary cell culture paradigm, we identified a role of Slitrk2 and Slitrk5 in the post-synaptic regulation of excitatory and inhibitory synaptogenesis, respectively. The perturbation of mDA neurons’ electrophysiological activity, resulting from Slitrk2/5 loss or gain of function could lead to an alteration in dopamine release to mDA neurons target nuclei, and thus to the development of pathological behaviours associated with human neuropsychiatric diseases.|
|Document Type:||Mémoire de maîtrise|
|Open Access Date:||24 April 2018|
|Collection:||Thèses et mémoires|
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