ROBERTA GIOIA

Dottoressa di ricerca

ciclo: XXXIII


co-supervisore: Emanuele Cacci

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.

Produzione scientifica

  • 11573/1088312 - 2017 - Terminal differentiation of adult hippocampal progenitor cells is a step functionally dissociable from proliferation and is controlled by Tis21, Id3 and NeuroD2 (01a Articolo in rivista)
    CECCARELLI CALCAGNI, MANUELA; GIOIA, ROBERTA; CESTARI, VINCENZO
  • 11573/1117185 - 2018 - Egr1 maintains NSC proliferation and its overexpression counteracts cell cycle exit triggered by the withdrawal of Epidermal Growth Factor (01a Articolo in rivista)
    CERA, ARCANGELA ANNA; CACCI, EMANUELE; TOSELLI, CAMILLA; CARDARELLI, SILVIA; BERNARDI, ALESSANDRA; GIOIA, ROBERTA; GIORGI, MAURO; POIANA, GIANCARLO; BIAGIONI, STEFANO
  • 11573/1235452 - 2019 - Molecular mechanisms of neurogenic aging in the adult mouse subventricular zone (01a Articolo in rivista)
    LUPO, GIUSEPPE; GIOIA, ROBERTA; NISI, PAOLA SERENA; BIAGIONI, STEFANO; CACCI, EMANUELE
  • 11573/1347065 - 2019 - Neural stem cell properties and adult hippocampal neurogenesis in a knock-in mice model, expressing an autism-associated mutation. (04f Poster)
    GIOIA, ROBERTA; TROBIANI, LAURA; DI MATTIA, MIRIAM; BIAGIONI, STEFANO; DE JACO, ANTONELLA; CACCI, EMANUELE
  • 11573/1348015 - 2020 - Transcriptional regulation of adult neural stem/progenitor cells: tales from the subventricular zone (01a Articolo in rivista)
    POIANA, GIANCARLO; GIOIA, ROBERTA; SINERI, SERENA; CARDARELLI, SILVIA; LUPO, GIUSEPPE; CACCI, EMANUELE
  • 11573/1668215 - 2023 - Adult hippocampal neurogenesis and social behavioural deficits in the R451C Neuroligin3 mouse model of autism are reverted by the antidepressant Fluoxetine (01a Articolo in rivista)
    GIOIA, ROBERTA; SERI, TOMMASO; DIAMANTI, TAMARA; BIAGIONI, STEFANO; LUPO, GIUSEPPE; RINALDI, ARIANNA; DE JACO, ANTONELLA; CACCI, EMANUELE

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