Speranza, Luisa (2014) The Serotonin Receptor 7: a key regulator of neuronal cytoarchitecture in the Central Nervous System. [Tesi di dottorato]

Anteprima

Testo tesi dottorato Luisa Speranza marzo 2014.pdf Download (11MB) | Anteprima

Abstract

In the last decade, a number of results show the involvement of 5-HT7 receptor in many aspects of neuronal development, such as neurite outgrowth, modulation of neuronal morphology and changes of dendritic spine shape and density. In particular, it was demonstrated that stimulation of endogenous receptor in embryonic hippocampal neurons resulted in a marked elongation of neurites (Kvanchina et al., 2005). In addition, the activation of 5-HT7R/G12 signaling pathway in postnatal hippocampal cultures promotes formation of dendritic protrusion, synaptogenesis and modulates synaptic plasticity (Kobe et al., 2012). In line with these results, my PhD project aims at characterizing the role of 5-HT7 receptor in remodeling neuronal cyto-architecture and connectivity during the early and late development, in behavioral relevant CNS circuits. The comprehension of the molecular basis of 5-HT7 receptor involvement in modulation of neuronal connectivity is important to understand whether the pharmacological modulation of this receptor may improve a number of neurodevelopmental diseases carachterized by altered connectivity (e.g., X-fragile, ADHD, Rett syndrome). Here I show that stimulation of 5-HT7R with the selective agonist LP-211 promotes extensive neurite elongation in striatal, cortical and hippocampal embryonic primary cultures. These effects are inhibited by the selective 5-HT7 receptor antagonist SB-269970. This neurite outgrowth requires the activation of ERK1/2 and Cdk5 and is sustained by qualitative and quantitative changes of selected neuronal cytoskeletal proteins (i.e. actin, MAP1B, cofilin). In addition, using specifically designed microfluidic chambers, I also demonstrate that stimulation of hippocampal neurons with LP-211 significantly enhances axonal elongation. Furthermore, preliminary results show that stimulation of 5-HT7 receptor, in vivo in adult mice, modulates dendritic spine morphology in the CNS. Finally, the 5-HT7 receptor stimulation partially rescues the morphological alterations of mouse cortical embryonic primary cultures obtained from Mecp2-/y animal model, which recapitulates a severe form of mental retardation characterized by altered cerebral connectivity, the Rett syndrome. Taken together, these results highlight the key role played by 5-HT7 receptor in the regulation of neuronal cytoarchitecture and may provide insights for innovative pharmacological treatments of neurodevelopmental disorders characterized by altered brain connectivity.

Downloads

Actions (login required)

Modifica documento