COSENTINO LIVIA

PhD Graduate

PhD program:: XXXIII



Thesis title: The role of the methyl-CpG binding protein 2 (MECP2) in shaping vulnerability for psychopathology

Exposure to trauma is a common experience worldwide, which may lead to multiple adverse consequences for physical and mental health, and is compulsory for the diagnosis of post-traumatic stress disorder (PTSD), a chronic mental disorder characterized by symptoms of persistent anxiety and hypervigilance. Considering the key role played by susceptibility in determining the outcome of traumatic experiences, and the well-documented contribution of epigenetic mechanisms in the establishment of interindividual differences in PTSD risk and resilience, this dissertation aimed at translationally addressing the potential contribution of the X-linked epigenetic regulator methyl-CpG binding protein 2 (MECP2) in shaping vulnerability to develop stress and trauma-related disorders. With this goal, taking advantage of a transgenic mouse line, we evaluated whether disruptions in MeCP2 functionality may predispose to the onset of PTSD-like symptomatology in the aftermath of a traumatic event. Male mice constitutively expressing a hypofunctional form of MeCP2 protein and exposed to unescapable footshocks displayed exaggerated fear and increased avoidance of trauma cues, overgeneralization of fear responses and altered circadian rhythms, mimicking the psychopathological symptoms experienced by patients. Also, traumatized mutants displayed peripheral alterations in gene expression mirroring patterns already evidenced in people suffering from PTSD. Interestingly, although mutant females displayed similar disruptions in fear memory compared to males, sex-dependent alterations in stress responsivity were evidenced among mutants, with females releasing lower and males higher levels of glucocorticoids compared to sex-matched wild type (wt) controls. At the brain level, a region- and sex- specific pattern of stress-related alterations in gene expression was found. We also aimed at confirming that reduced MECP2 functionality was associated with increased stress vulnerability in human cohorts. This issue was addressed in two different studies. The first including healthy participants, explored the link between blood MECP2 expression and childhood adversities, and addressed its effect on symptoms of depression and anxiety, which could confer vulnerability to stress-related disorders. The second study focused on the evaluation of blood MECP2 levels in PTSD patients and healthy traumatized and non-traumatized controls, with or without stress during childhood, and their correlation with the severity of PTSD symptomatology. In the first study we found that decreased MECP2 expression was indirectly associated with increased depressed mood and trait anxiety in healthy participants, a correlation mediated by childhood stress and moderated by gender. In line with this, in the second study we observed that childhood stress mediated the association between decreased MECP2 expression and increased PTSD symptom severity in traumatized participants, especially among women, further corroborating a role for MECP2 downregulation in promoting trauma vulnerability. Interestingly, men traumatized at adulthood overexpressed MECP2, independently from the severity of childhood stress. Overall, the present work presents strong evidence for the role of decreased MECP2 functionality in boosting susceptibility to develop PTSD in the aftermath of traumatic experiences, opening to the possibility that MECP2-related epigenetic pathways might be involved in the etiology of the disorder. Importantly, gender emerges as an important modulator of the association between MECP2 and PTSD susceptibility.

Research products

  • 11573/1179718 - 2016 - Genes and sex hormones interaction in neurodevelopmental disorders (01g Articolo di rassegna (Review))
    COSENTINO, LIVIA
  • 11573/1174112 - 2019 - Rescue of prepulse inhibition deficit and brain mitochondrial dysfunction by pharmacological stimulation of the central serotonin receptor 7 in a mouse model of CDKL5 deficiency disorder (01a Articolo in rivista)
    VIGLI, DANIELE; COSENTINO, LIVIA
  • 11573/1174107 - 2018 - Chronic treatment with the phytocannabinoid cannabidivarin (CBDV) rescues behavioural alterations and brain atrophy in a mouse model of rett syndrome (01a Articolo in rivista)
    VIGLI, DANIELE; COSENTINO, LIVIA
  • 11573/1227091 - 2018 - MECP2 mutant mice: a new animal model for susceptibility to traumatic events (04d Abstract in atti di convegno)
    COSENTINO, LIVIA; VIGLI, DANIELE
  • 11573/1227092 - 2018 - MECP2 mutant mice: a new animal model for susceptibility to traumatic events (04d Abstract in atti di convegno)
    COSENTINO, LIVIA; VIGLI, DANIELE
  • 11573/1227093 - 2018 - Prepulse inhibition defects and brain mitochondrial dysfunctions are rescued by selective stimulation of serotonin receptor 7 in a mouse model of CDKL5 Deficiency Disorder. (04d Abstract in atti di convegno)
    VIGLI, DANIELE; COSENTINO, LIVIA
  • 11573/1227096 - 2018 - Pharmacological stimulation of 5-HT7 receptor rescues Sensory-motor gating and emotional memory-associative learning function in MeCP2-308 female mice. (04d Abstract in atti di convegno)
    VIGLI, DANIELE; COSENTINO, LIVIA
  • 11573/1227097 - 2018 - The phytocannabinoid cannabidivarin (CBDV) rescues behavioural alterations and brainatrophy in Mecp2-308 hemizygous male mice (04d Abstract in atti di convegno)
    VIGLI, DANIELE; COSENTINO, LIVIA
  • 11573/1227100 - 2019 - Trauma-exposed methyl-CpG binding protein 2 mutant mice: a new animal model for post-traumatic stress disorder (04d Abstract in atti di convegno)
    COSENTINO, LIVIA; VIGLI, DANIELE; LUCARELLI, MARCO; FUSO, ANDREA
  • 11573/1227101 - 2019 - Alterations in Methyl-CpG binding protein 2 functionality provide vulnerability to traumatic events (04d Abstract in atti di convegno)
    COSENTINO, LIVIA; LUCARELLI, MARCO; FUSO, ANDREA
  • 11573/1227090 - 2018 - Pharmacological stimulation of the central serotonin receptor 7 rescues prepulse inhibition deficit and brain mitochondrial dysfunction in a mouse model of CDKL5 disorder (04d Abstract in atti di convegno)
    VIGLI, DANIELE; COSENTINO, LIVIA
  • 11573/1227089 - 2018 - Behavioural alterations and brain atrophy are rescued by chronic treatment with the phytocannabinoid, Cannabidivarin (CBDV), in a mouse model of Rett syndrome (04d Abstract in atti di convegno)
    VIGLI, DANIELE; COSENTINO, LIVIA
  • 11573/1227082 - 2017 - Stimulation of the brain serotonin receptor 7 rescues sensory motor gating impairments, emotional memory deficits and brain mithocondrial dysfunction in a mouse model of Rett Syndrome (04d Abstract in atti di convegno)
    VIGLI, DANIELE; COSENTINO, LIVIA
  • 11573/1227074 - 2017 - Characterization of the estrous cycle in female mice modelling Rett syndrome (04d Abstract in atti di convegno)
    COSENTINO, LIVIA; VIGLI, DANIELE
  • 11573/1286407 - 2019 - Methyl-CpG binding protein 2 (MeCP2) dysfunction provides vulnerability to traumatic events in male mice (04d Abstract in atti di convegno)
    COSENTINO, LIVIA; VIGLI, DANIELE; LUCARELLI, MARCO; FUSO, ANDREA
  • 11573/1286404 - 2019 - Pharmacological stimulation of the serotonin receptor 7 substantially rescues behavioral, physiological and brain molecular alterations in a female mouse model of Rett syndrome (04d Abstract in atti di convegno)
    VIGLI, DANIELE; NAPOLETANI, GIORGIA; COSENTINO, LIVIA; GRIECO, MADDALENA; FUSO, ANDREA; D'ERME, MARIA
  • 11573/1286403 - 2019 - Group I p21-activated kinases as innovative therapeutic targets for CDKL5 Deficiency Disorder. (04d Abstract in atti di convegno)
    COSENTINO, LIVIA
  • 11573/1286405 - 2019 - Pharmacological inhibition of p21-Activated Kinase rescues the behavioural phenotype in a female mouse model of CDKL5 Deficiency Disorder (04d Abstract in atti di convegno)
    URBINATI, CHIARA; COSENTINO, LIVIA
  • 11573/1286384 - 2019 - Rett syndrome before regression: a time window of overlooked opportunities for diagnosis and intervention (01g Articolo di rassegna (Review))
    COSENTINO, LIVIA; VIGLI, DANIELE
  • 11573/1286409 - 2019 - MeCP2 aberrant functionality interacts with sex in shaping stress effects on cognitive functions (04d Abstract in atti di convegno)
    COSENTINO, LIVIA; VIGLI, DANIELE
  • 11573/1286396 - 2019 - Stress affects cognitive functions through an interplay between MeCP2 and sex (04d Abstract in atti di convegno)
    COSENTINO, LIVIA; VIGLI, DANIELE
  • 11573/1348645 - 2019 - Pharmacological inhibition of p21-Activated Kinase rescues the behavioral phenotype in a female mouse model of CDKL5 Deficiency Disorder (04d Abstract in atti di convegno)
    URBINATI, CHIARA; COSENTINO, LIVIA
  • 11573/1348652 - 2019 - Systemic treatment with Rimonabant, a CB1 receptor antagonist, improves behavioural alterations in a mouse model of Rett syndrome (04d Abstract in atti di convegno)
    COSENTINO, LIVIA; VIGLI, DANIELE
  • 11573/1348637 - 2019 - Male mice carrying dysfunctional methyl-CpG binding protein 2 are vulnerable to traumas (04d Abstract in atti di convegno)
    COSENTINO, LIVIA; VIGLI, DANIELE; LUCARELLI, MARCO; FUSO, ANDREA
  • 11573/1406171 - 2020 - Potential therapeutic value of the anti-diabetic drug metformin in a mouse model of Rett syndrome: a preclinical study (04d Abstract in atti di convegno)
    URBINATI, CHIARA; ZULIANI, ILARIA; COSENTINO, LIVIA; DI DOMENICO, FABIO; PERLUIGI, MARZIA
  • 11573/1406139 - 2020 - The anti-diabetic drug metformin rescues aberrant mitochondrial activity and restrains oxidative stress in a female mouse model of rett syndrome (01a Articolo in rivista)
    ZULIANI, ILARIA; URBINATI, CHIARA; COSENTINO, LIVIA; DI DOMENICO, FABIO; PERLUIGI, MARZIA
  • 11573/1406172 - 2020 - LP-211 persistently rescues neurobehavioral and physiological impairments via epigenetic modulation of brain histone acetylation in a mouse model of Rett syndrome (04d Abstract in atti di convegno)
    COSENTINO, LIVIA; NAPOLETANI, GIORGIA; VIGLI, DANIELE; GRIECO, MADDALENA; FUSO, ANDREA; D'ERME, MARIA
  • 11573/1487099 - 2020 - MECP2: a sex dependent actor in stress regulation of memory (04d Abstract in atti di convegno)
    COSENTINO, LIVIA; URBINATI, CHIARA
  • 11573/1489007 - 2020 - P.861Gender-specific involvement of Methyl-CpG binding protein 2 in vulnerability to stress: evidence from a healthy cohort (01h Abstract in rivista)
    COSENTINO, LIVIA
  • 11573/1488991 - 2021 - Chronic treatment with cannabidiolic acid (CBDA) reduces thermal pain sensitivity in male mice and rescues the hyperalgesia in a mouse model of rett syndrome (01a Articolo in rivista)
    VIGLI, DANIELE; COSENTINO, LIVIA
  • 11573/1539694 - 2021 - Methyl-CpG binding protein 2 dysfunction provides stress vulnerability with sex- and zygosity-dependent outcomes (01a Articolo in rivista)
    COSENTINO, LIVIA; VIGLI, DANIELE
  • 11573/1539692 - 2021 - Stimulation of the serotonin receptor 7 restores brain histone H3 acetylation and MeCP2 corepressor protein levels in a female mouse model of Rett syndrome (01a Articolo in rivista)
    NAPOLETANI, GIORGIA; VIGLI, DANIELE; COSENTINO, LIVIA; GRIECO, MADDALENA; FUSO, ANDREA; D'ERME, MARIA
  • 11573/1282147 - 2019 - Methyl-CpG binding protein 2 functional alterations provide vulnerability to develop behavioral and molecular features of post-traumatic stress disorder in male mice (01a Articolo in rivista)
    COSENTINO, LIVIA; VIGLI, DANIELE; LUCARELLI, MARCO; FUSO, ANDREA
  • 11573/1519774 - 2021 - P.219 The antidiabetic drug metformin improves cognitive flexibility deficits in a female mouse model of Rett syndrome (01h Abstract in rivista)
    URBINATI, CHIARA; COSENTINO, LIVIA
  • 11573/1605799 - 2021 - Treatment with the bacterial toxin CNF1 selectively rescues cognitive and brain mitochondrial deficits in a female mouse model of Rett syndrome carrying a MeCP2-null mutation (01a Articolo in rivista)
    URBINATI, CHIARA; COSENTINO, LIVIA; VIGLI, DANIELE
  • 11573/1605803 - 2021 - Long-term treatment with the antidiabetic drug metformin ameliorates cognitive flexibility deficits in a female mouse model of Rett syndrome. (04d Abstract in atti di convegno)
    URBINATI, CHIARA; COSENTINO, LIVIA
  • 11573/1605805 - 2021 - The first-line antidiabetic drug Metformin improves the impaired cognitive flexibility in a female mouse model of Rett syndrome. (04d Abstract in atti di convegno)
    URBINATI, CHIARA; COSENTINO, LIVIA
  • 11573/1672908 - 2022 - Treatment with the CB1R antagonist rimonabant rescues brain mitochondrial dysfunction via inhibition of intra-mitochondrial protein kinase A signalling in a mouse model of Rett syndrome (04d Abstract in atti di convegno)
    URBINATI, CHIARA; COSENTINO, LIVIA
  • 11573/1657453 - 2022 - Serotonin receptor 7 stimulation rescues fear generalization in a male mouse model of post-traumatic stress disorder (04c Atto di convegno in rivista)
    COSENTINO, LIVIA; URBINATI, CHIARA
  • 11573/1406167 - 2020 - Inhibition of p21-activated kinase rescues disrupted phenotype in a mouse model of CDKL5 deficiency disorder (04c Atto di convegno in rivista)
    COSENTINO, LIVIA
  • 11573/1672906 - 2022 - Pharmacological stimulation of the serotonin receptor 7 rescues fear generalization in a PTSD mouse model carrying a truncated form of MeCP2. (04d Abstract in atti di convegno)
    COSENTINO, LIVIA; URBINATI, CHIARA
  • 11573/1406176 - 2020 - Fight, flight or freeze? MECP2 involvement in choosing the strategy to cope with stress (04d Abstract in atti di convegno)
    COSENTINO, LIVIA
  • 11573/1348640 - 2019 - Metformin treatment rescues aberrant mitochondrial activity and oxidative stress status in the brain of female mouse model of Rett syndrome (04d Abstract in atti di convegno)
    URBINATI, CHIARA; ZULIANI, ILARIA; COSENTINO, LIVIA; VIGLI, DANIELE; DI DOMENICO, FABIO; PERLUIGI, MARZIA
  • 11573/1657450 - 2022 - Treatment with FRAX486 rescues neurobehavioral and metabolic alterations in a female mouse model of CDKL5 deficiency disorder (01a Articolo in rivista)
    COSENTINO, LIVIA; URBINATI, CHIARA; FUSO, ANDREA
  • 11573/1657452 - 2021 - Pharmacological stimulation of the serotonin receptor 7 rescues PTSD-like behavioural alterations in male mice carrying a truncated form of mecp2. (04d Abstract in atti di convegno)
    COSENTINO, LIVIA; URBINATI, CHIARA

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