Dottorato in BIOLOGIA CELLULARE E DELLO SVILUPPO

Titolo della tesi: Neural stem cell properties and adult hippocampal neurogenesis in R451C Neuroligin3 mouse, a monogenic model of Autism spectrum disorder

Adult neurogenesis is a process that occurs in physiological conditions, and its alteration has been associated with neuropsychiatric disorders. Adult neural stem/progenitor cells (NSPCs) pool and new neurons formation in the hippocampus were found altered in mice expressing susceptibility genes associated with autism spectrum disorder (ASD), suggesting that some of the behavioral deficits in these mice may be linked with deregulated neurogenesis. Among these genes, Neuroligins are involved in several forms of monogenic ASD and they encode for postsynaptic cell adhesion proteins implicated in the maturation, specification, and plasticity of synapsis. R451C Neuroligin 3 (Nlgn3) knock-in mice displayed deficits in synaptic functions, structural brain abnormalities and behavioral alteration resembling some of the ASD features. Here we show the impact of this specific mutation in Nlgn3 gene on adult neurogenesis, focusing on the subgranular zone of the hippocampal dentate gyrus (DG), a neurogenic niche of the adult brain, with both in vivo and in vitro approaches. We found a reduction of immature and mature new neurons formation in the ventral DG of knock-in mice, rescued by fluoxetine treatment, used as a pro-neurogenic stimulus. The treatment ameliorates behavioral deficit found in this model, involving the activation of new neurons produced and integrated into existing circuits. Moreover, in vitro cultures of hippocampal NSPCs showed a differential increase in Nlgn protein levels during differentiation in wild-type and knock-in cells and an altered differentiation capability in vitro, with an increase in the number of neurons in knock-in cultures. Additionally, we found a Nlgn3 reduction and the UPR activation in knock-in cells, as previously shown in transformed cell lines. Our data provide the first evidence of neurogenesis alteration in R451C KI mice and demonstrate that modulation of adult neurogenesis with pro-neurogenic factors could ameliorate behavioral deficits, strengthen the potential correlations of adult neurogenesis dysfunctions with neurodevelopmental disorders.