Unbalance between Excitation and Inhibition in Phenylketonuria, a Genetic Metabolic Disease Associated with Autism

Phenylketonuria (PKU) is the most common genetic metabolic disease with a well-documented association with autism spectrum disorders. It is characterized by the deficiency of the phenylalanine hydroxylase activity, causing plasmatic hyperphenylalaninemia and variable neurological and cognitive impairments. Among the potential pathophysiological mechanisms implicated in autism spectrum disorders is the excitation/inhibition (E/I) imbalance which might result from alterations in excitatory/inhibitory synapse development, synaptic transmission and plasticity, downstream signalling pathways, and intrinsic neuronal excitability. Here, we investigated functional and molecular alterations in the prefrontal cortex (pFC) of BTBR-Pah(enu2) (ENU2) mice, the animal model of PKU. Our data show higher frequency of inhibitory transmissions and significant reduced frequency of excitatory transmissions in the PKU-affected mice in comparison to wild type. Moreover, in the pFC of ENU2 mice, we reported higher levels of the post-synaptic cell-adhesion proteins neuroligin1 and 2. Altogether, our data point toward an imbalance in the E/I neurotransmission favouring inhibition in the pFC of ENU2 mice, along with alterations of the molecular components involved in the organization of cortical synapse. In addition to being the first evidence of E/I imbalance within cortical areas of a mouse model of PKU, our study provides further evidence of E/I imbalance in animal models of pathology associated with autism spectrum disorders

Targeting mGlu5 metabotropic glutamate receptors in the treatment of cognitive dysfunction in a mouse model of phenylketonuria

We studied group-I metabotropic glutamate (mGlu) receptors in Pah(enu2) (ENU2) mice, which mimic the genetics and neurobiology of human phenylketonuria (PKU), a metabolic disorder characterized, if untreated, by autism, and intellectual disability (ID). Male ENU2 mice showed increased mGlu5 receptor protein levels in the hippocampus and corpus striatum (but not in the prefrontal cortex) whereas the transcript of the mGlu5 receptor was unchanged. No changes in mGlu1 receptor mRNA and protein levels were found in any of the three brain regions of ENU2 mice. We extended the analysis to Homer proteins, which act as scaffolds by linking mGlu1 and mGlu5 receptors to effector proteins. Expression of the long isoforms of Homer was significantly reduced in the hippocampus of ENU2 mice, whereas levels of the short Homer isoform (Homer 1a) were unchanged. mGlu5 receptors were less associated to immunoprecipitated Homer in the hippocampus of ENU2 mice. The lack of mGlu5 receptor-mediated long-term depression (LTD) in wild-type mice (of BTBR strain) precluded the analysis of hippocampal synaptic plasticity in ENU2 mice. We therefore performed a behavioral analysis to examine whether pharmacological blockade of mGlu5 receptors could correct behavioral abnormalities in ENU2 mice. Using the same apparatus we sequentially assessed locomotor activity, object exploration, and spatial object recognition (spatial novelty test) after displacing some of the objects from their original position in the arena. Systemic treatment with the mGlu5 receptor antagonist, MPEP (20 mg/kg, i.p.), had a striking effect in the spatial novelty test by substantially increasing the time spent in exploring the displaced objects in ENU2 mice (but not in wild-type mice). These suggest a role for mGlu5 receptors in the pathophysiology of ID in PKU and suggest that, also in adult untreated animals, cognitive dysfunction may be improved by targeting these receptors with an appropriate therapy

Il cinema di Zhang Yimou

Quando nel 1988 Sorgo rosso vince l’Orso d’oro al Festival di Berlino, Zhang Yimou fa già parte, insieme ad altri registi cinesi, della cosiddetta Quinta generazione, il movimento di giovani talenti che tentano di innovare il cinema del proprio paese a partire dalla prima metà degli anni Ottanta. In breve tempo Zhang diviene il regista cinese più conosciuto al mondo grazie a film come Lanterne rosse (Leone d’argento al Festival di Venezia del 1991) e La storia di Qiu Ju (Leone d’oro 1992). La sua poetica, all’insegna della sperimentazione degli stili e dei generi, e allo stesso tempo improntata alla classicità del linguaggio e della narrazione cinematografica, delinea un profilo autoriale che riesce nel difficile compito di coniugare creazione colta di universi cinematografici sofisticati e autoreferenziali e desiderio artigianale di narrare storie per il più ampio numero di spettatori possibile. Un cinema, insomma, che parla direttamente ai cinesi ma non disdegna di rivolgersi al pubblico di tutto il mondo, e che fa leva su due costanti: la centralità dell’individuo e la fiducia nella sempre attuale modernità delle «ombre elettriche»

Static, dynamic and impact properties of a high-performance flax-fiber composite

As environmental issues become increasingly relevant nowadays, the need to develop new materials entirely or partially based on renewable resources is one fundamental step to reduce the consumption of fossil fuels and CO2 emissions. In that sense, natural fiber composites might represent an environmentally sustainable alternative to conventional solutions such as glass and carbon fiber composites, standard today for many lightweight structural applications; however, solutions are several and diverse in terms of technological process, base materials, mechanical properties, and analysis of their behaviour, necessary for safe industrial use, is still lacking for most resin-fiber combinations. Consequently, this work presents a comprehensive material characterization of a flax-fiber reinforced composite material, analyzing both the static and dynamic mechanical performances, targeting future crashworthiness applications. In particular static tensile, compressive, flexural and shear properties were investigated, while low-speed indentation, high strain-rate tensile and ballistic tests were carried out to probe the dynamic and impact features