Novel molecular and pharmacological regulators of Neural Stem Cells in physiological and disease mechanisms

Neural Stem Cells (NSC) perform a very important role during brain development as they are involved in the formation of the main neuronal circuitry contributing to the entire brain structural and functional formation. These cells persist even in discrete regions of adult mammalian brain such as the subgranular zone of the dentate gyrus. In the adult hippocampus, NSC and newborn neurons confer an extra degree of neural plasticity, which likely contributes to crucial brain functions such as learning, memory and mood regulation. Alteration in NSC properties, principally proliferation and neuronal differentiation, during brain development stage could strongly affect brain formation. In fact, patients with the Down syndrome (DS), a neurodevelopmental disorder due to chromosome 21 trisomy, show a reduced NSC proliferation and neurogenesis before prenatal stage and important deficits in higher cognitive functions, such as learning and memory. It was demonstrated in animal model that early treatments could restore neural defect in DS. In such respect, we want to identify novel clinically relevant drugs that could modulate neonatal neurogenesis with the aim to develop the potential therapies for DS patients. However, deregulation of neurogenesis in adult brain has even been demonstrated in several neurodegenerative disorders, including the major depression. Major depression is one of the areas where adult hippocampal neurogenesis is extensively studied. Several preclinical studies indicate that chronic administration of antidepressant drugs results in enhanced neurogenesis in the adult rodent and human DG. This opens the possibility that modulation of adult neurogenesis may contribute to the therapeutic effects of these drugs also in the clinical setting. However, it is unknown the contribution of different serotoninergic receptors in the proneurogenic effect mediated by antidepressants. In such respect, we investigate in detail the role of serotonin signalling in the regulation of adult hippocampal neurogenesis