1,339 research outputs found
Study of new potential therapeutic approaches for the Rett syndrome in murine models
No full textRett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. RTT is caused by mutations in either the MECP2 or CDKL5 gene. Currently there is no cure for this devastating disorder. The present thesis investigated the potential therapeutic efficacy of two different molecules on RTT mice carrying mutations in MeCP2 or Cdkl5 gene: LP-211, an agonist of serotonin receptor 7 (5-HT7R) and Cannabidivarin (CBDV), new phytocannabinoid under investigation in the clinical setting, which targets the G protein-coupled receptor 55 (GPR55). Our results demonstrate that LP-211 rescue a wide range of behavioural and brain molecular alterations both in MeCP2 and Cdkl5-mutated mice. New clues on the possible mechanism of LP-211 action are provided. The present thesis also demonstrates that in MeCP2-mutated mice the chronic CBDV treatment rescues many important behavioural alterations; moreover, we suggest a possible mechanism of action for CBDV, proposing brain GPR55 as a new pharmacological target for RTT treatment. Despite further studies are needed to clarify the link between RTT and the serotoninergic and/or the endocannabinoid system, the present thesis suggests innovative targets and two promising pharmacological approaches for the treatment of patients affected by this severe disorder
Methyl‐CpG binding protein 2 dysfunction provides stress vulnerability with sex‐ and zygosity‐dependent outcomes
No full textStress 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
Stimulation of the brain serotonin receptor 7 rescues mitochondrial dysfunction in female mice from two models of Rett syndrome
No full textRett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that neurobehavioral and brain molecular alterations can be rescued in a RTT mouse model, by pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family, crucially involved in the regulation of brain structural plasticity and cognitive processes, can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective agonist. The present study extends previous findings by demonstrating that LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues mitochondrial respiratory chain impairment, oxidative phosphorylation deficiency and the reduced energy status in the brain of heterozygous female mice from two highly validated mouse models of RTT (MeCP2-308 and MeCP2-Bird mice). Moreover, LP-211 treatment completely restored the radical species overproduction by brain mitochondria in the MeCP2-308 model and partially recovered the oxidative imbalance in the more severely affected MeCP2-Bird model. These results provide the first evidence that RTT brain mitochondrial dysfunction can be rescued targeting the brain 5-HT7R and add compelling preclinical evidence of the potential therapeutic value of LP-211 as a pharmacological approach for this devastating neurodevelopmental disorder
Maternal immune activation in mice only partially recapitulates the autism spectrum disorders symptomatology
No full textPrenatal viral/bacterial infections are considered risk factors for autism spectrum disorders (ASD) and rodent models of maternal immune activation (MIA) have been developed and extensively used in preclinical studies. Poly inosinic-cytidylic acid (Poly I:C) was injected in C57BL6/J dams to mimic a viral infection on gestational day 12.5; the experimental design includes 10/12 litters in each treatment group and data were analysed always considering the litter-effect; neonatal (spontaneous motor behaviour and ultrasonic vocalizations) and adult [open field, marble burying, social approach, fear conditioning, prepulse inhibition (PPI)] offspring of both sexes were tested. In vivo magnetic resonance imaging/spectroscopy (MRI-MRS) and high-performance liquid chromatography (HPLC) to quantify both aminoacid and/or neurotransmitter concentration in cortical and striatal regions were also carried out. In both sexes high levels of repetitive motor responses and sensory gating deficits in PPI were the more striking effects of Poly I:C, whereas no alteration of social responses were evidenced. Poly I:C treatment did not affect mean values, but, intriguingly, increased variability in the levels of four aminoacids (aspartate glycine and GABA) selectively in males. As a whole prenatal Poly I:C induced relevant long-term alterations in explorative-stereotyped motor responses and in sensory gating, sparing cognitive and social competences. When systematically assessing differences between male and female siblings within each litter, no significant sex differences were evident except for increased variability of four aminoacid levels in male brains. As a whole, prenatal Poly I:C paradigms appear to be a useful tool to investigate the profound and translationally-relevant effects of developmental immune activation on brain and behavioural development, not necessarily recapitulating the full ASD symptomatolog
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
No full textPerspettiva ridotta a perfezione: Glimpses of Daniele Barbaro’s Perspective Theory
No full textThis contribution is intended to identify some textual elements, apparently
secondary in Daniele Barbaro’s treatise on perspective, which either foreshadow
unprecedented developments in the discipline of representation or have
constituted complex critical nodes in the field of perspective. The first of these
is introduced in part V: anamorphosis (though never so called by the author, since
the term was not yet in use), suggesting a quick method to deform any flat image
by means of shadows. Finally, the author mentions two other ‘eccentric’ elements
of interest for the future developments of perspective that originated in Daniele
Barbaro’s text: an optical-projective device first introduced by Giovanni Battista
Vimercato, later developed by Jean François Niceron in his Thaumaturgus
opticus (1646), and the camera obscura
INTRUSION AND PRESENCE OF THE AUTHOR IN SAMUEL BECKETT’S “THE UNNAMABLE” AND B. S. JOHNSON’S “ALBERT ANGELO”
No full textThis article explores the intricate relationship between B.S. Johnson’s novel “Albert Angelo” and Beckett’s “The Unnamable”, both dealing with the issue of the possible presence of the author in his own text. The point of departure for such comparison is Johnson’s incorporation, as an epigraph, of a passage taken from Beckett’s novel. Such passage, intended rather literally by the British author, is employed as a justification not only for the central device at the heart of his novel, but also in support of a larger aesthetic project which will characterise a great part of his oeuvre – which famously stresses the importance of ‘truth’, as opposed to fabulation, and the necessity of the author’s direct presence in his texts. This contribution, in particular, tries to reconstruct the history of Johnson’s involvement with Beckett’s work, demonstrating how Johnson has in fact distorted the master’s message – perhaps intentionally – in order to produce a rather different model of literature, despite moving from very similar premises
Recensione di Daniele Vecchiato: Versi per dopodomani. Percorsi di lettura nell’opera di Durs Grünbein
No full textDaniele Vecchiato offers a clear excursus on the reception of Durs Grünbein. This is the first study in Italy about this famous contemporary author that was also influenced greatly by Italian culture and literature
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