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Presynaptic increase in striatal dopamine is the primary dopaminergic abnormality in schizophrenia, but the underlying mechanisms are not understood. Here, we hypothesized that increased expression of endogenous GDNF could induce dopaminergic abnormalities that resemble those seen in schizophrenia. To test the impact of GDNF elevation, without inducing adverse effects caused by ectopic overexpression, we developed a novel in vivo approach to conditionally increase endogenous GDNF expression. We found that a 2–3-fold increase in endogenous GDNF in the brain was sufficient to induce molecular, cellular, and functional changes in dopamine signalling in the striatum and prefrontal cortex, including increased striatal presynaptic dopamine levels and reduction of dopamine in prefrontal cortex. Mechanistically, we identified adenosine A2a receptor (A2AR), a G-protein coupled receptor that modulates dopaminergic signalling, as a possible mediator of GDNF-driven dopaminergic abnormalities. We further showed that pharmacological inhibition of A2AR with istradefylline partially normalised striatal GDNF and striatal and cortical dopamine levels in mice. Lastly, we found that GDNF levels are increased in the cerebrospinal fluid of first episode psychosis patients, and in post-mortem striatum of schizophrenia patients. Our results reveal a possible contributor for increased striatal dopamine signalling in a subgroup of schizophrenia patients and suggest that GDNF—A2AR crosstalk may regulate dopamine function in a therapeutically targetable manner.

Glial cell line-derived neurotrophic factor (GDNF) supports function and survival of dopamine neurons that degenerate in Parkinson’s disease (PD). Ectopic delivery of GDNF in clinical trials to treat PD is safe but lacks significant therapeutic effect. In pre-clinical models, ectopic GDNF is effective but causes adverse effects, including downregulation of tyrosine hydroxylase, only a transient boost in dopamine metabolism, aberrant neuronal sprouting, and hyperactivity. Hindering development of GDNF mimetic increased signaling via GDNF receptor RET by activating mutations results in cancer. Safe and effective mode of action must be defined first in animal models to develop successful GDNF-based therapies. Previously we showed that about a 2-fold increase in endogenous GDNF expression is safe and results in increased motor and dopaminergic function and protection in a PD model in young animals. Recently, similar results were reported using a novel Gdnf mRNA-targeting strategy. Next, it is important to establish the safety of a long-term increase in endogenous GDNF expression. We report behavioral, dopamine system, and cancer analysis of five cohorts of aged mice with a 2-fold increase in endogenous GDNF. We found a sustained increase in dopamine levels, improvement in motor learning, and no side effects or cancer. These results support the rationale for further development of endogenous GDNF-based treatments and GDNF mimetic., Graphical Abstract, Ectopic GDNF delivery raises concerns about efficacy in clinical trials of Parkinson’s disease and safety issues in preclinical studies. Andressoo and colleagues showed that a long-term, 2-fold increase in endogenous GDNF levels in mice is safe and improves motor and dopaminergic system function, supporting further development of endogenous GDNF-based therapies.

Activation of mitochondrial metabolism and proteostasis with the NAD+ precursor nicotinamide riboside (NR) has emerged as a potential therapeutic approach for neurodegenerative disorders including Parkinson’s disease (PD). However, despite recently started clinical trials, studies on NR in animal models of PD are scarce. In this study, we investigated the effect of NR in multiple models of PD. In transgenic C. elegans overexpressing α-synuclein, a protein of which aggregation is believed to promote PD, NR rescued PD-like phenotypes including mitochondrial dysfunction and motility defects, decreased oxidative stress, and age-related dopamine (DA) neuron loss. We found that NR eased symptoms of disease by activating the mitochondrial unfolded protein response (UPRmt) via the transcription factor atfs-1. Similarly, in a proteasome inhibitor, lactacystin, -induced mouse model of PD, NR rescued mitochondrial dysfunction and behavioural deficits caused by lactacystin lesion. However, long-term NR supplementation, in conjunction with proteasome inhibition, resulted in decreased DA levels in both the lesioned and unlesioned sides of the substantia nigra with concomitant downregulation of key genes in DA metabolism. Our results suggest specific endpoints that should be monitored in ongoing NR clinical trials.

Currently available genetic tools do not allow researchers to upregulate (‘Knock Up’) the levels of a given protein while retaining its cell-type-specific regulation. As a result, we have limited ability to develop overexpression-related disease models, to study the contribution of single genes in diseases caused by copy number variations and to identify disease pathways for drug targets. Here we develop two approaches for endogenous gene upregulation:conditionalKnockUp (cKU) utilizing the Cre/lox system, and CRISPR-Cas9 mediated geneKnockUp (KU) in wild-type mouse embryos and human cells. Using glial cell line derived neurotrophic factor (GDNF) as a proof of concept, we show that both approaches resulted in upregulation of endogenous GDNF levels without disturbingGdnf’s expression pattern. Furthermore, CNS-specific GDNF cKU resulted in dopaminergic abnormalities and schizophrenia-like phenotypes. Our results suggest that gene Knock Up can reveal unknown gene functions and provide novel entry points for studying neurological disease.

Spesso gli amministratori locali hanno la necessità di valutare le implicazioni della concessione di spazi e contribuzioni ad associazioni e gruppi organizzati del territorio (enti del Terzo Settore, associazioni sportive, ecc.). Tale valutazione non è facile, se correlata esclusivamente a una tradizionale visione di un bilancio basato su aspetti contabili. Allo scopo, gli autori hanno messo a punto il “Bilancio in Valore” (BiV), che affianca, non sostituendolo, quello tradizionale, ma che tiene conto di aspetti rilevanti non di tipo contabile. Il BiV considera, oltre alle normali entrate e uscite, anche: • misure “monetizzate” di entrate e uscite che non corrispondono a movimenti contabili (volontariato, comodati d’uso, ecc.); • misure monetizzabili con difficoltà, ma valutabili attraverso i loro effetti su base statistica (riduzione di costi sanitari, riduzione di costi legati al disagio, ecc.); • indicatori di rilevanza sociale, non misurabili economicamente (benessere sociale, attenzione all’altro, cultura, ecc.). Ne emerge uno strumento che funge da bussola per le scelte politiche, decisivo per le amministrazioni locali che intendano operare con consapevolezza, e certamente utile nella gestione dei rapporti tra la Pubblica Amministrazione e gli enti del Terzo Settore. Le metodiche trattate sono state verificate sul campo. La trattazione è preceduta da un’ampia dissertazione che dimostra come misure basate solo su fattori economici non siano adeguate alle decisioni strategiche di una Pubblica Amministrazione che deve, invece, avere obiettivi molto più ampi verso il “ben-essere” per l’individuo e per la collettività. Ne emerge un vero e proprio manifesto politico di cui il Bilancio in Valore è strumento portante.

International audience; Altered neuronal network formation and function involving dysregulated excitatory and inhibitory circuits are associated with fragile X syndrome (FXS). We examined functional maturation of the excitatory transmission system in FXS by investigating the response of FXS patient-derived neural progenitor cells to the glutamate analog (AMPA). Neural progenitors derived from induced pluripotent stem cell (iPSC) lines generated from boys with FXS had augmented intracellular Ca 2+ responses to AMPA and kainate that were mediated by Ca 2+-permeable AMPA receptors (CP-AMPARs) lacking the GluA2 subunit. Together with the enhanced differentiation of glutamate-responsive cells, the proportion of CP-AMPAR and N-methyl-d-aspartate (NMDA) receptor-coexpressing cells was increased in human FXS progenitors. Differentiation of cells lacking GluA2 was also increased and paralleled the increased inward rectification in neural progenitors derived from Fmr1-knockout mice (the FXS mouse model). Human FXS progenitors had increased the expression of the precursor and mature forms of miR-181a, a microRNA that represses translation of the transcript encoding GluA2. Blocking GluA2-lacking, CP-AMPARs reduced the neurite length of human iPSC-derived control progenitors and further reduced the shortened length of neurites in human FXS progenitors, supporting the contribution of CP-AMPARs to the regulation of progenitor differentiation. Furthermore , we observed reduced expression of Gria2 (the GluA2-encoding gene) in the frontal lobe of FXS mice, consistent with functional changes of AMPARs in FXS. Increased Ca 2+ influx through CP-AMPARs may increase the vulnerability and affect the differentiation and migration of distinct cell populations, which may interfere with normal circuit formation in FXS.

Summary The absence of FMR1 protein (FMRP) causes fragile X syndrome (FXS) and disturbed FMRP function is implicated in several forms of human psychopathology. We show that intracellular calcium responses to depolarization are augmented in neural progenitors derived from human induced pluripotent stem cells and mouse brain with FXS. Increased calcium influx via nifedipine-sensitive voltage-gated calcium (Cav) channels contributes to the exaggerated responses to depolarization and type 1 metabotropic glutamate receptor activation. The ratio of L-type/T-type Cav channel expression is increased in FXS progenitors and correlates with enhanced progenitor differentiation to glutamate-responsive cells. Genetic reduction of brain-derived neurotrophic factor in FXS mouse progenitors diminishes the expression of Cav channels and activity-dependent responses, which are associated with increased phosphorylation of the phospholipase C-γ1 site within TrkB receptors and changes of differentiating progenitor subpopulations. Our results show developmental effects of increased calcium influx via L-type Cav channels in FXS neural progenitors., Highlights • Responses to activity are augmented in neural progenitors in fragile X syndrome (FXS). • Increased Ca2+ influx contributes to the exaggerated FXS progenitor responses • L-type voltage-gated channels are abnormally activated in FXS progenitors • Reduced BDNF diminishes Ca2+ influx and modulates FXS progenitor differentiation, In this article, Maija Castrén and colleagues show contribution of increased Ca2+ influx through L-type voltage-gated calcium channels to augmented responses to depolarization and glutamate receptor activation in neural progenitors derived from human induced pluripotent stem cells (iPSCs) and mouse brain modeling fragile X syndrome.

Charts the progress of the introduction of a quality information system at telecommunication manufacturer Italtel. Highlights the system′s role as a tool in a TQM programme whose aim is to create a common information base for all aspects of the organisation. Details the types of database and reports available on components, processes and products throughout their lifecycle. Illustrates quality reporting mechanisms for procurement, production, systems in the field and a variety of cost assessment reporting procedures.