Publications by authors named "Livia Cosentino"

10 Publications

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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.

Int J Mol Sci 2021 Jun 23;22(13). Epub 2021 Jun 23.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy.

Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked 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 gene (MeCP2-308 mice). Given the heterogeneity of 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.
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http://dx.doi.org/10.3390/ijms22136739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269120PMC
June 2021

Methyl-CpG binding protein 2 dysfunction provides stress vulnerability with sex- and zygosity-dependent outcomes.

Eur J Neurosci 2021 Mar 2. Epub 2021 Mar 2.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy.

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. Although heterozygous females displayed a normal stress-related behavioural 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, whereas blunted in mutant females in a zygosity-independent manner. Although 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, whereas heterozygosity does not lead to maladaptive stress outcomes. MeCP2 dysfunctions thus provide stress vulnerability in mice with sex- and zygosity-dependent outcomes.
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http://dx.doi.org/10.1111/ejn.15165DOI Listing
March 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.

J Neuropathol Exp Neurol 2021 Feb;80(3):265-273

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Roma, Italy.

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.
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http://dx.doi.org/10.1093/jnen/nlaa158DOI Listing
February 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.

Neuroscience 2021 01 30;453:113-123. Epub 2020 Sep 30.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuroscience.2020.09.041DOI Listing
January 2021

The Anti-Diabetic Drug Metformin Rescues Aberrant Mitochondrial Activity and Restrains Oxidative Stress in a Female Mouse Model of Rett Syndrome.

J Clin Med 2020 Jun 1;9(6). Epub 2020 Jun 1.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy.

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.
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http://dx.doi.org/10.3390/jcm9061669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355965PMC
June 2020

Methyl-CpG binding protein 2 functional alterations provide vulnerability to develop behavioral and molecular features of post-traumatic stress disorder in male mice.

Neuropharmacology 2019 12 6;160:107664. Epub 2019 Jun 6.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuropharm.2019.06.003DOI Listing
December 2019

Rett syndrome before regression: A time window of overlooked opportunities for diagnosis and intervention.

Neurosci Biobehav Rev 2019 12 18;107:115-135. Epub 2019 May 18.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neubiorev.2019.05.013DOI Listing
December 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.

Neuropharmacology 2019 01 13;144:104-114. Epub 2018 Oct 13.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy. Electronic address:

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-HTR) 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-HTR.
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http://dx.doi.org/10.1016/j.neuropharm.2018.10.018DOI Listing
January 2019

Chronic treatment with the phytocannabinoid Cannabidivarin (CBDV) rescues behavioural alterations and brain atrophy in a mouse model of Rett syndrome.

Neuropharmacology 2018 09 27;140:121-129. Epub 2018 Jul 27.

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuropharm.2018.07.029DOI Listing
September 2018

Genes and sex hormones interaction in neurodevelopmental disorders.

Neurosci Biobehav Rev 2016 Aug 4;67:9-24. Epub 2016 Mar 4.

Dept. Cell Biology and Neuroscience, Istituto Superiore di Sanità, Roma, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neubiorev.2016.02.019DOI Listing
August 2016
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