Livia Cosentino
@iss.it
PhD, Center for Behavioral Sciences and Mental Health
Istituto Superiore di Sanità
RESEARCH INTERESTS
Rett Syndrome, Epigenetics, PTSD, Stress, Vulnerability, Prevention, Early Diagnosis, Gender differences, Machine Learning, Deep Learning, Computer Vision
Scopus Publications
Scopus Publications
Livia Cosentino, Stephanie H. Witt, Helene Dukal, Francesca Zidda, Sebastian Siehl, Herta Flor, and Bianca De Filippis
Springer Science and Business Media LLC
AbstractTraumatic events may lead to post-traumatic stress disorder (PTSD), with higher prevalence in women. Adverse childhood experiences (ACE) increase PTSD risk in adulthood. Epigenetic mechanisms play important roles in PTSD pathogenesis and a mutation in the methyl-CpG binding protein 2 (MECP2) in mice provide susceptibility to PTSD-like alterations, with sex-dependent biological signatures. The present study examined whether the increased risk of PTSD associated with ACE exposure is accompanied by reduced MECP2 blood levels in humans, with an influence of sex. MECP2 mRNA levels were analyzed in the blood of 132 subjects (58 women). Participants were interviewed to assess PTSD symptomatology, and asked to retrospectively report ACE. Among trauma-exposed women, MECP2 downregulation was associated with the intensification of PTSD symptoms linked to ACE exposure. MECP2 expression emerges as a potential contributor to post-trauma pathophysiology fostering novel studies on the molecular mechanisms underlying its potential sex-dependent role in PTSD onset and progression.
Camilla Cittadini, Elena Angela Pia Germinario, Zaira Maroccia, Livia Cosentino, Valeria Maselli, Lucrezia Gambardella, Massimo Giambenedetti, Marco Guidotti, Sara Travaglione, Chiara Fallerini,et al.
Wiley
The bacterial product CNF1, through its action on the Rho GTPases, is emerging as a modulator of crucial signalling pathways involved in selected neurological diseases characterized by mitochondrial dysfunctions. Mitochondrial impairment has been hypothesized to have a key role in paramount mechanisms underlying Rett syndrome (RTT), a severe neurologic rare disorder. CNF1 has been already reported to have beneficial effects in mouse models of RTT. Using human RTT fibroblasts from four patients carrying different mutations, as a reliable disease-in-a-dish model, we explored the cellular and molecular mechanisms, which can underlie the CNF1-induced amelioration of RTT deficits. We found that CNF1 treatment modulates the Rho GTPases activity of RTT fibroblasts and induces a considerable re-organization of the actin cytoskeleton, mainly in stress fibres. Mitochondria of RTT fibroblasts show a hyperfused morphology and CNF1 decreases the mitochondrial mass leaving substantially unaltered the mitochondrial dynamic. From a functional perspective, CNF1 induces mitochondrial membrane potential depolarization and activation of AKT in RTT fibroblasts. Given that mitochondrial quality control is altered in RTT, our results are suggestive of a reactivation of the damaged mitochondria removal via mitophagy restoration. These effects can be at the basis of the beneficial effects of CNF1 in RTT.
Chiara Urbinati, Chiara Lanzillotta, Livia Cosentino, Daniela Valenti, Maria Cristina Quattrini, Livia Di Crescenzo, Francesca Prestia, Donatella Pietraforte, Marzia Perluigi, Fabio Di Domenico,et al.
Elsevier BV
Livia Cosentino, Francesca Zidda, Helene Dukal, Stephanie H. Witt, Bianca De Filippis, and Herta Flor
Springer Science and Business Media LLC
AbstractNumerous mental illnesses arise following stressful events in vulnerable individuals, with females being generally more affected than males. Adverse childhood experiences are known to increase the risk of developing psychopathologies and DNA methylation was demonstrated to drive the long-lasting effects of early life stress and promote stress susceptibility. Methyl-CpG binding protein 2 (MECP2), an X-linked reader of the DNA methylome, is altered in many mental disorders of stress origin, suggesting MECP2 as a marker of stress susceptibility; previous works also suggest a link between MECP2 and early stress experiences. The present work explored whether a reduced expression of MECP2 is paralleled by an increased vulnerability to the negative outcomes of stress exposure during childhood. To this aim, blood MECP2 mRNA levels were analyzed in 63 people without history of mental disorders and traits pertaining to depressive and anxiety symptom clusters were assessed as proxies of the vulnerability to develop stress-related disorders; stress exposure during childhood was also evaluated. Using structural equation modeling, we demonstrate that reduced MECP2 expression is accompanied by symptoms of anxiety/depression in association with exposure to stress in early life, selectively in healthy women. These results suggest a gender-specific involvement of MECP2 in the maladaptive outcomes of childhood adversities, and shed new light on the complex biology underlying gender bias in stress susceptibility.
Claudia Fuchs, Livia Cosentino, Chiara Urbinati, Maria Cristina Talamo, Giorgio Medici, Maria Cristina Quattrini, Nicola Mottolese, Donatella Pietraforte, Andrea Fuso, Elisabetta Ciani,et al.
Wiley
INTRODUCTION
CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental condition, primarily affecting girls for which no cure currently exists. Neuronal morphogenesis and plasticity impairments as well as metabolic dysfunctions occur in CDD patients. The present study explored the potential therapeutic value for CDD of FRAX486, a brain-penetrant molecule that was reported to selectively inhibit group I p21-activated kinases (PAKs), serine/threonine kinases critically involved in the regulation of neuronal morphology and glucose homeostasis.
METHODS
The effects of treatment with FRAX486 on CDD-related alterations were assessed in vitro (100 nM for 48 h) on primary hippocampal cultures from Cdkl5-knockout male mice (Cdkl5-KO) and in vivo (20 mg/Kg, s.c. for 5 days) on Cdkl5-KO heterozygous females (Cdkl5-Het).
RESULTS
The in vitro treatment with FRAX486 completely rescued the abnormal neuronal maturation and the number of PSD95-positive puncta in Cdkl5-KO mouse neurons. In vivo, FRAX486 normalized the general health status, the hyperactive profile and the fear learning defects of fully symptomatic Cdkl5-Het mice. Systemically, FRAX486 treatment normalized the levels of reactive oxidizing species in the whole blood and the fasting-induced hypoglycemia displayed by Cdkl5-Het mice. In the hippocampus of Cdkl5-Het mice, treatment with FRAX486 rescued spine maturation and PSD95 expression and restored the abnormal PAKs phosphorylation at sites which are critical for their activation (P-PAK-Ser144/141/139) or for the control cytoskeleton remodeling (P-PAK1-Thr212).
CONCLUSIONS
Present results provide evidence that PAKs may represent innovative therapeutic targets for CDD.
Livia Cosentino, Fabio Bellia, Nicole Pavoncello, Daniele Vigli, Claudio D'Addario, and Bianca De Filippis
Wiley
Stress vulnerability is a critical factor for the development of trauma-related disorders, however its biological underpinnings are not clear. We demonstrated that dysfunctions in the X-linked epigenetic factor methyl-CpG binding protein 2 (MeCP2) provide trauma vulnerability in male mice. Given the prominent role of sex in stress outcomes, we explored the effects of MeCP2 hypofunctionality in females. Female mice carrying truncated MeCP2 (heterozygous and homozygous) and wild type controls (wt) were tested for fear memory. Stress-induced corticosterone release and brain expression of hypothalamic-pituitary-adrenal (HPA) axis regulatory genes were also evaluated in wt and mutant mice of both sexes. While heterozygous females displayed a normal stress-related behavioral profile, homozygous mice showed enhanced memory recall for the threatening context compared to wt, thus recapitulating the phenotype previously evidenced in hemizygous males. Interestingly, MeCP2 truncation abolished the sex differences in stress-induced corticosterone release, which was found increased in mutant males, while blunted in mutant females in a zygosity-independent manner. While heterozygous mice did not differ from controls, homozygous females and hemizygous males showed increased hypotalamic Crh and Avp mRNAs and a differentially altered expression of Fkbp5 in cortical areas. Present results demonstrate that in female mice carrying truncated MeCP2 altered stress responsivity is driven by homozygosity, while heterozygosity does not lead to maladaptive stress outcomes. MeCP2 dysfunctions thus provide stress vulnerability in mice with sex- and zygosity-dependent outcomes.
Chiara Urbinati, Livia Cosentino, Elena Angela Pia Germinario, Daniela Valenti, Daniele Vigli, Laura Ricceri, Giovanni Laviola, Carla Fiorentini, Rosa Anna Vacca, Alessia Fabbri,et al.
MDPI AG
Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene and a major cause of intellectual disability in females. No cure exists for RTT. We previously reported that the behavioural phenotype and brain mitochondria dysfunction are widely rescued by a single intracerebroventricular injection of the bacterial toxin CNF1 in a RTT mouse model carrying a truncating mutation of the MeCP2 gene (MeCP2-308 mice). Given the heterogeneity of MECP2 mutations in RTT patients, we tested the CNF1 therapeutic efficacy in a mouse model carrying a null mutation (MeCP2-Bird mice). CNF1 selectively rescued cognitive defects, without improving other RTT-related behavioural alterations, and restored brain mitochondrial respiratory chain complex activity in MeCP2-Bird mice. To shed light on the molecular mechanisms underlying the differential CNF1 effects on the behavioural phenotype, we compared treatment effects on relevant signalling cascades in the brain of the two RTT models. CNF1 provided a significant boost of the mTOR activation in MeCP2-308 hippocampus, which was not observed in the MeCP2-Bird model, possibly explaining the differential effects of CNF1. These results demonstrate that CNF1 efficacy depends on the mutation beared by MeCP2-mutated mice, stressing the need of testing potential therapeutic approaches across RTT models.
Giorgia Napoletani, Daniele Vigli, Livia Cosentino, Maddalena Grieco, Maria Cristina Talamo, Enza Lacivita, Marcello Leopoldo, Giovanni Laviola, Andrea Fuso, Maria d’Erme,et al.
Oxford University Press (OUP)
Abstract Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene, characterized by severe behavioral and physiological impairments for which no cure is available. The stimulation of serotonin receptor 7 (5-HT7R) with its selective agonist LP-211 (0.25 mg/kg/day for 7 days) was proved to rescue neurobehavioral alterations in a mouse model of RTT. In the present study, we aimed at gaining insight into the mechanisms underpinning the efficacy of 5-HT7R pharmacological stimulation by investigating its epigenetic outcomes in the brain of RTT female mice bearing a truncating MeCP2 mutation. Treatment with LP-211 normalized the reduced histone H3 acetylation and HDAC3/NCoR levels, and increased HDAC1/Sin3a expression in RTT mouse cortex. Repeated 5-HT7R stimulation also appeared to strengthen the association between NCoR and MeCP2 in the same brain region. A different profile was found in RTT hippocampus, where LP-211 rescued H3 hyperacetylation and increased HDAC3 levels. Overall, the present data highlight a new scenario on the relationship between histone acetylation and serotoninergic pathways. 5-HT7R is confirmed as a pivotal therapeutic target for the recovery of neuronal function supporting the translational value of this promising pharmacological approach for RTT.
Daniele Vigli, Livia Cosentino, Mattia Pellas, and Bianca De Filippis
Elsevier BV
Rett syndrome (RTT) is a rare neurologic disorder, characterized by severe behavioural and physiological symptoms. RTT is caused by mutations in the MECP2 gene in about 95% of cases and to date no cure is available. Recent evidence suggests that non-euphoric phytocannabinoids (pCBs) extracted from Cannabis sativa may represent innovative therapeutic molecules for RTT, with the cannabinoid cannabidivarin having beneficial effects on behavioural and brain molecular alterations in RTT mouse models. The present study evaluated the potential therapeutic efficacy for RTT of cannabidiolic acid (CBDA; 0.2, 2, 20 mg/kg through intraperitoneal injections for 14 days), a pCB that has proved to be effective for the treatment of nausea and anxiety in rodents. This study demonstrates that systemic treatment with the low dose of CBDA has anti-nociceptive effects and reduces the thermal hyperalgesia in 8-month old MeCP2-308 male mice, a validated RTT mouse model. CBDA did not affect other behavioural or molecular parameters. These results provide support to the antinociceptive effects of CBDA and stress the need for further studies aimed at clarifying the mechanisms underlying the abnormal pain perception in RTT.
Ilaria Zuliani, Chiara Urbinati, Daniela Valenti, Maria Cristina Quattrini, Vanessa Medici, Livia Cosentino, Donatella Pietraforte, Fabio Di Domenico, Marzia Perluigi, Rosa Anna Vacca,et al.
MDPI AG
Metformin is the first-line therapy for diabetes, even in children, and a promising attractive candidate for drug repurposing. Mitochondria are emerging as crucial targets of metformin action both in the periphery and in the brain. The present study evaluated whether treatment with metformin may rescue brain mitochondrial alterations and contrast the increased oxidative stress in a validated mouse model of Rett syndrome (RTT), a rare neurologic disorder of monogenic origin characterized by severe behavioral and physiological symptoms. No cure for RTT is available. In fully symptomatic RTT mice (12 months old MeCP2-308 heterozygous female mice), systemic treatment with metformin (100 mg/kg ip for 10 days) normalized the reduced mitochondrial ATP production and ATP levels in the whole-brain, reduced brain oxidative damage, and rescued the increased production of reactive oxidizing species in blood. A 10-day long treatment with metformin also boosted pathways related to mitochondrial biogenesis and antioxidant defense in the brain of metformin-treated RTT mice. This treatment regimen did not improve general health status and motor dysfunction in RTT mice at an advanced stage of the disease. Present results provide evidence that systemic treatment with metformin may represent a novel, repurposable therapeutic strategy for RTT.
Livia Cosentino, Daniele Vigli, Vanessa Medici, Herta Flor, Marco Lucarelli, Andrea Fuso, and Bianca De Filippis
Elsevier BV
Post-traumatic stress disorder (PTSD) is a mental disorder characterized by symptoms of persistent anxiety arising after exposure to traumatic events. Stress susceptibility due to a complex interplay between genetic and environmental factors plays a major role in the disease etiology, although biological underpinnings have not been clarified. We hypothesized that aberrant functionality of the methyl-CpG binding protein 2 (MECP2), a master regulator of experience-dependent epigenetic programming, confers susceptibility to develop PTSD-like symptomatology in the aftermath of traumatic events. Transgenic male mice expressing a truncated form of MeCP2 protein (MeCP2-308) were exposed at adulthood to a trauma in the form of high-intensity footshocks. The presence and duration of PTSD-like symptoms were assessed and compared to those of trauma-exposed wild type littermates and MeCP2-308 mice subjected to a mild stressor. The effects of fluoxetine, a prime pharmacological PTSD treatment, on PTSD-like symptomatology were also explored. Trauma-exposed MeCP2-308 mice showed long-lasting hyperresponsiveness to both correct and incorrect predictors of the trauma and persistent increased avoidance of trauma-related cues. Traumatized MeCP2-308 mice also displayed abnormal post-traumatic plasma levels of the stress hormone corticosterone and altered peripheral gene expression mirroring that of PTSD patients. Fluoxetine improved PTSD-like symptoms in trauma-exposed MeCP2-308 mice. These findings provide evidence that MeCP2 dysfunction results in increased susceptibility to develop PTSD-like symptoms after trauma exposure, and identify trauma-exposed MeCP2-308 mice as a new tool to investigate the underpinnings of PTSD vulnerability.
Livia Cosentino, Daniele Vigli, Francesca Franchi, Giovanni Laviola, and Bianca De Filippis
Elsevier BV
Rett syndrome (RTT) is a rare neurological disorder primarily affecting females, causing severe cognitive, social, motor and physiological impairments for which no cure currently exists. RTT clinical diagnosis is based on the peculiar progression of the disease, since patients show an apparently normal initial development with a subsequent sudden regression at around 2 years of age. Accumulating evidences are rising doubts regarding the absence of early impairments, hence questioning the concept of regression. We reviewed the published literature addressing the pre-symptomatic stage of the disease in both patients and animal models with a particular focus on behavioral, physiological and brain abnormalities. The emerging picture delineates subtle, but reliable impairments that precede the onset of overt symptoms whose bases are likely set up already during embryogenesis. Some of the outlined alterations appear transient, suggesting compensatory mechanisms to occur in the course of development. There is urgent need for more systematic developmental analyses able to detect early pathological markers to be used as diagnostic tools and precocious targets of time-specific interventions.
Daniele Vigli, Laura Rusconi, Daniela Valenti, Paolo La Montanara, Livia Cosentino, Enza Lacivita, Marcello Leopoldo, Elena Amendola, Cornelius Gross, Nicoletta Landsberger,et al.
Elsevier BV
&NA; Mutations in the X‐linked cyclin‐dependent kinase‐like 5 (CDKL5) gene cause CDKL5 Deficiency Disorder (CDD), a rare neurodevelopmental syndrome characterized by severe behavioural and physiological symptoms. No cure is available for CDD. CDKL5 is a kinase that is abundantly expressed in the brain and plays a critical role in neurodevelopmental processes, such as neuronal morphogenesis and plasticity. This study provides the first characterization of the neurobehavioural phenotype of 1 year old Cdkl5‐null mice and demonstrates that stimulation of the serotonin receptor 7 (5‐HT7R) with the agonist molecule LP‐211 (0.25 mg/kg once/day for 7 days) partially rescues the abnormal phenotype and brain molecular alterations in Cdkl5‐null male mice. In particular, LP‐211 treatment completely normalizes the prepulse inhibition defects observed in Cdkl5‐null mice and, at a molecular level, restores the abnormal cortical phosphorylation of rpS6, a downstream target of mTOR and S6 kinase, which plays a direct role in regulating protein synthesis. Moreover, we demonstrate for the first time that mitochondria show prominent functional abnormalities in Cdkl5‐null mouse brains that can be restored by pharmacological stimulation of brain 5‐HT7R. HIGHLIGHTSCharacterization of behavioural phenotype in fully symptomatic Cdkl5‐null mice.The 5HT7R agonist LP‐211 normalizes prepulse inhibition defects in Cdkl5‐null mice.LP‐211 treatment rescues brain mitochondrial dysfunction in Cdkl5‐null mice.The abnormal phosphorylation of rpS6 in Cdkl5‐null cortex is restored by LP‐211.
Daniele Vigli, Livia Cosentino, Carla Raggi, Giovanni Laviola, Marie Woolley-Roberts, and Bianca De Filippis
Elsevier BV
Abstract Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. RTT is caused by mutations in the MECP2 gene in about 95% of cases and to date no cure is available. The endocannabinoid system modulates several physiological processes and behavioural responses that are impaired in RTT and its deregulation has been associated with neuropsychiatric disorders which have symptoms in common with RTT. The present study evaluated the potential therapeutic efficacy for RTT of cannabidivarin (CBDV), a non‐psychotropic phytocannabinoid from Cannabis sativa that presents antagonistic properties on the G protein‐coupled receptor 55 (GPR55), the most recently identified cannabinoid receptor. Present results demonstrate that systemic treatment with CBDV (2, 20, 100 mg/Kg ip for 14 days) rescues behavioural and brain alterations in MeCP2‐308 male mice, a validated RTT model. The CBDV treatment restored the compromised general health status, the sociability and the brain weight in RTT mice. A partial restoration of motor coordination was also observed. Moreover, increased levels of GPR55 were found in RTT mouse hippocampus, suggesting this G protein‐coupled receptor as new potential target for the treatment of this disorder. Present findings highlight for the first time for RTT the translational relevance of CBDV, an innovative therapeutic agent that is under active investigation in the clinical setting. HighlightsThe CBDV treatment improved the general health in a mouse model for Rett syndrome.The CBDV treatment rescued the deficit in sociability in a mouse model for Rett syndrome.The CBDV treatment improved motor coordination in a mouse model for Rett syndrome.The CBDV treatment normalized the brain weight in a mouse model for Rett syndrome.GPR55 levels were increased in hippocampus of a mouse model for Rett syndrome.
Emilia Romano, Livia Cosentino, Giovanni Laviola, and Bianca De Filippis
Elsevier BV
The prevalence, age of onset and symptomatology of many neurodevelopmental disorders strongly differ between genders. This review examines sex biases in human neurodevelopmental disorders and in validated animal models. A focus is made on disorders of well-established genetic origin, such as Rett syndrome, CDKL5-associated disorders, Fragile X and Down syndrome. Autism is also addressed, given its paradigmatic role as a sex-biased neurodevelopmental disorder. Reviewed literature confirms that a complex interaction between genetic factors and sex hormones may underlie the differential susceptibility of genders and may impact the severity of symptoms in most of the analyzed neurodevelopmental disorders. Even though further studies addressing the advantages and disadvantages conferred by biological sex in this class of disorders are needed to disentangle the underlying mechanisms, present findings suggest that modulation of sex steroid-related pathways may represent an innovative approach for these diseases. Much effort is now expected to unravel the potential therapeutic efficacy of drugs targeting sex hormones-related signaling pathways in neurodevelopmental disorders of well-established genetic origin.