European Brain Research Institute Rita Levi Montalcini

Rome, Italy

European Brain Research Institute Rita Levi Montalcini

Rome, Italy
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Ambrosini A.,IRCCS NeuromedPozzilli Isernia Italy | D'Onofrio M.,European Brain Research Institute Rita Levi Montalcini | Buzzi M.G.,IRCCS Santa Lucia FoundationRome Italy | Arisi I.,European Brain Research Institute Rita Levi Montalcini | And 3 more authors.
Headache | Year: 2017

Objective: To search for differences in prevalence of a CACNA1E variant between migraine without aura, various phenotypes of migraine with aura, and healthy controls. Background: Familial hemiplegic migraine type 1 (FHM1) is associated with mutations in the CACNA1A gene coding for the alpha 1A (Cav2.1) pore-forming subunit of P/Q voltage-dependent Ca2+ channels. These mutations are not found in the common forms of migraine with or without aura. The alpha 1E subunit (Cav2.3) is the counterpart of Cav2.1 in R-type Ca2+ channels, has different functional properties, and is encoded by the CACNA1E gene. Methods: First, we performed a total exon sequencing of the CACNA1E gene in three probands selected because they had no abnormalities in the three FHM genes. In a patient suffering from basilar-type migraine, we identified a single nucleotide polymorphism (SNP) in exon 20 of the CACNA1E gene (Asp859Glu - rs35737760; Minor Allele Frequency 0.2241) hitherto not studied in migraine. In a second step, we determined its occurrence in four groups by direct sequencing on blood genomic DNA: migraine patients without aura (N=24), with typical aura (N=55), complex neurological auras (N=19; hemiplegic aura: N=15; brain stem aura: N=4), and healthy controls (N=102). Results: The Asp859Glu - rs35737760 SNP of the CACNA1E gene was present in 12.7% of control subjects and in 20.4% of the total migraine group. In the migraine group it was significantly over-represented in patients with complex neurological auras (42.1%), OR 4.98 (95% CI: 1.69-14.67, uncorrected P=.005, Bonferroni P=.030, 2-tailed Fisher's exact test). There was no significant difference between migraine with typical aura (10.9%) and controls. Conclusions: We identified a polymorphism in exon 20 of the CACNA1E gene (Asp859Glu - rs35737760) that is more prevalent in hemiplegic and brain stem aura migraine. This missense variant causes a change from aspartate to glutamate at position 859 of the Cav2.3 protein and might modulate the function of R-type Ca2+ channels. It could thus be relevant for migraine with complex neurological aura, although this remains to be proven. © 2017 American Headache Society.


Cattaneo A.,European Brain Research Institute Rita Levi Montalcini | Cattaneo A.,Normal School of Pisa | Calissano P.,European Brain Research Institute Rita Levi Montalcini
Molecular Neurobiology | Year: 2012

Understanding sporadic Alzheimer's disease (AD) onset and progression requires an explanation of what triggers the common core of abnormal processing of the amyloid precursor protein and tau processing. In the quest for upstream drivers of sporadic, late-onset AD neurodegeneration, nerve growth factor (NGF) has a central role. Initially connected to AD on a purely correlative basis, because of its neurotrophic actions on basal forebrain cholinergic neurons, two independent lines of research, reviewed in this article, place alterations of NGF processing and signaling at the center stage of a new mechanism, leading to the activation of amyloidogenesis and tau processing. Thus, experimental studies on NGF deficit induced neurodegeneration in transgenic mice, as well as the mechanistic studies on the anti-amyloidogenic actions of NGF/TrkA signaling in primary neuronal cultures demonstrated a novel causal link between neurotrophic signaling deficits and Alzheimer's neurodegeneration. Around these results, a new NGF hypothesis can be built, with neurotrophic deficits of various types representing an upstream driver of the core AD triad pathology. According to the new NGF hypothesis for AD, therapies aimed at reestablishing a correct homeostatic balance between ligands (and receptors) of the NGF pathway appear to have a clear and strong rationale, not just as long-term cholinergic neuroprotection, but also as a truly disease-modifying approach. © 2012 Springer Science+Business Media, LLC.


Bianchi D.,University of Rome La Sapienza | Marasco A.,University of Naples Federico II | Limongiello A.,University of Naples Federico II | Marchetti C.,European Brain Research Institute Rita Levi Montalcini | And 4 more authors.
Journal of Computational Neuroscience | Year: 2012

Under sustained input current of increasing strength neurons eventually stop firing, entering a depolarization block. This is a robust effect that is not usually explored in experiments or explicitly implemented or tested in models. However, the range of current strength needed for a depolarization block could be easily reached with a random background activity of only a few hundred excitatory synapses. Depolarization block may thus be an important property of neurons that should be better characterized in experiments and explicitly taken into account in models at all implementation scales. Here we analyze the spiking dynamics of CA1 pyramidal neuron models using the same set of ionic currents on both an accurate morphological reconstruction and on its reduction to a singlecompartment. The results show the specific ion channel properties and kinetics that are needed to reproduce the experimental findings, and how their interplay can drastically modulate the neuronal dynamics and the input current range leading to a depolarization block. We suggest that this can be one of the rate-limiting mechanisms protecting a CA1 neuron from excessive spiking activity. © Springer Science+Business Media, LLC 2012.


Sgritta M.,University of Pavia | Sgritta M.,European Brain Research Institute Rita Levi Montalcini | Locatelli F.,University of Pavia | Soda T.,University of Pavia | And 3 more authors.
Journal of Neuroscience | Year: 2017

Spike-timing dependent plasticity (STDP) is a form of long-term synaptic plasticity exploiting the time relationship between postsynaptic action potentials (AP) and EPSPs. Surprisingly enough, very little was known about STDP in the cerebellum, although it is thought to play a critical role for learning appropriate timing of actions. We speculated that low-frequency oscillations observed in the granular layer may provide a reference for repetitive EPSP/AP phase coupling. Here we show that EPSP-spike pairing at 6Hz can optimally induce STDP at the mossy fiber - granule cell synapse in rats. Spike timing-dependent long-term potentiation and depression (st-LTP and st-LTD) were confined to a ±25 ms time-window. Since EPSPs led APs in st-LTP while APs led EPSPs in st-LTD, STDP was Hebbian in nature. STDP occurred at 6-10 Hz but vanished above 50 Hz or below 1 Hz (where only LTP or LTD occurred). STDP disappeared with randomized EPSP/AP pairing or high intracellular Ca2+buffering and its sign was inverted by GABA-A receptor activation. Both st-LTP and st-LTD required NMDA receptors, but st-LTP also required reinforcing signals mediated by mGluRs and intracellular calcium stores. Importantly, st-LTP and st-LTD were significantly larger than LTP and LTD obtained by modulating the frequency and duration of mossy fiber bursts, probably because STDP expression involved postsynaptic in addition to presynaptic mechanisms. These results thus show that a Hebbian form of STDP occurs at the cerebellum input stage providing the substrate for phase-dependent binding of mossy fiber spikes to repetitive theta-frequency cycles of granule cell activity. © 2017 the authors.


Cheung V.C.K.,Massachusetts Institute of Technology | DeBoer C.,Massachusetts Institute of Technology | Hanson E.,Massachusetts Institute of Technology | Tunesi M.,Polytechnic of Milan | And 5 more authors.
PLoS ONE | Year: 2013

The primary motor cortex (M1) supports motor skill learning, yet little is known about the genes that contribute to motor cortical plasticity. Such knowledge could identify candidate molecules whose targeting might enable a new understanding of motor cortical functions, and provide new drug targets for the treatment of diseases which impair motor function, such as ischemic stroke. Here, we assess changes in the motor-cortical transcriptome across different stages of motor skill acquisition. Adult rats were trained on a gradually acquired appetitive reach and grasp task that required different strategies for successful pellet retrieval, or a sham version of the task in which the rats received pellet reward without needing to develop the reach and grasp skill. Tissue was harvested from the forelimb motor-cortical area either before training commenced, prior to the initial rise in task performance, or at peak performance. Differential classes of gene expression were observed at the time point immediately preceding motor task improvement. Functional clustering revealed that gene expression changes were related to the synapse, development, intracellular signaling, and the fibroblast growth factor (FGF) family, with many modulated genes known to regulate synaptic plasticity, synaptogenesis, and cytoskeletal dynamics. The modulated expression of synaptic genes likely reflects ongoing network reorganization from commencement of training till the point of task improvement, suggesting that motor performance improves only after sufficient modifications in the cortical circuitry have accumulated. The regulated FGF-related genes may together contribute to M1 remodeling through their roles in synaptic growth and maturation. © 2013 Cheung et al.


D'Onofrio M.,European Brain Research Institute Rita Levi Montalcini | Arisi I.,European Brain Research Institute Rita Levi Montalcini | Brandi R.,European Brain Research Institute Rita Levi Montalcini | Di Mambro A.,European Brain Research Institute Rita Levi Montalcini | And 4 more authors.
Neurobiology of Aging | Year: 2011

We characterized the gene expression profile of brain regions at an early stage of the Alzheimer's like neurodegeneration in the anti-NGF AD11 model. Total RNA was extracted from hippocampus, cortex and basal forebrain of postnatal day 30 (P30) and postnatal day 90 (P90) mice and expression profiles were studied by microarray analysis, followed by qRT-PCR validation of 243 significant candidates. Wide changes in gene expression profiles occur already at P30. As expected, cholinergic system and neurotrophins related genes expression were altered. Interestingly, the most significantly affected clusters of mRNAs are linked to inflammation and immune response, as well as to Wnt signaling. mRNAs encoding for different complement factors show a large differential expression. This is noteworthy, since these complement cascade proteins are involved in CNS synapse elimination, during normal brain developing and in neurodegenerative diseases. This gene expression pattern highlights that an early event in AD11 neurodegeneration is represented, together with neurotrophic deficits and synaptic remodeling, by an inflammatory response and an unbalance in the immunotrophic state of the brain. These might be key events in the pathogenesis and development of AD. © 2009 Elsevier Inc.


Parisi C.,University of Rome La Sapienza | Giorgi C.,European Brain Research Institute Rita Levi Montalcini | Batassa E.M.,University of Rome La Sapienza | Braccini L.,University of Rome La Sapienza | And 9 more authors.
FEBS Letters | Year: 2011

Argonaute are a conserved class of proteins central to the microRNA pathway. We have highlighted a novel and non-redundant function of Ago1 versus Ago2; the two core factors of the miRNA-associated RISC complex. Stable overexpression of Ago1 in neuroblastoma cells causes the cell cycle to slow down, a decrease in cellular motility and a stronger apoptotic response upon UV irradiation. These effects, together with a significant increase in p53 levels, suggest that Ago1 may act as a tumor-suppressor factor, a function also supported by GEO Profiles microarrays that inversely correlate Ago1 expression levels with cell proliferation rates. © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.


Giorgi C.,European Brain Research Institute Rita Levi Montalcini | Cogoni C.,University of Rome La Sapienza | Catalanotto C.,University of Rome La Sapienza
Biomolecular Concepts | Year: 2012

Argonaute proteins play a central role in gene silencing pathways mediated by small RNA molecules. The ancestral function of small RNA-dependent silencing is related to genome protection against parasitic nucleic acids, such as transposons and viruses. However, new classes of small RNAs are continuously being uncovered in all higher eukaryotes in which they play important functions in processes ranging from embryonic development to differentiation to cell proliferation and metabolism. Small RNAs have variegated biogenesis pathways and accomplish distinct functions. Nevertheless, it appears that all small RNAs work merely as guides in recognizing the target RNAs invariably relying on the interaction with Argonaute proteins and associated factors for their biological function. Here, we discuss recent findings on the structure and regulation of mammalian Argonaute proteins and overview the various roles that these versatile proteins play in regulating gene expression. Copyright © by Walter de Gruyter.


Meli G.,European Brain Research Institute Rita Levi Montalcini | Krako N.,European Brain Research Institute Rita Levi Montalcini | Krako N.,Normal School of Pisa | Manca A.,European Brain Research Institute Rita Levi Montalcini | And 3 more authors.
Journal of Biological Regulators and Homeostatic Agents | Year: 2013

Several open questions call for new studies on pathogenic mechanisms leading to Alzheimer's Disease (AD), with the search for upstream drivers of the neurodegeneration cascade, such as neurotrophic deficits, early misfolding events of AD-related proteins (Aβ and tau) and understanding the multifactorial basis of AD pathogenesis. Since seminal immunosympathectomy experiment which represents the first example of a knock out experiment (albeit a protein knock-out), antibodies have had a long and successful history as a tool to selectively interfere with the function of proteins in cells and in organisms and antibody technologies represent a major weapon in the set of target validation techniques. Here, we describe a technology, pioneered by our group, based on recombinant antibody domains exploited as intracellular antibodies (intrabodies) whereby antibodies are used as genes, rather than as proteins. We discuss several applications and new promising developments of the intrabody approach for protein interference, especially in the field of AD research. Copyright © by BIOLIFE, s.a.s.


PubMed | European Brain Research Institute Rita Levi Montalcini
Type: Journal Article | Journal: Molecular neurobiology | Year: 2012

Understanding sporadic Alzheimers disease (AD) onset and progression requires an explanation of what triggers the common core of abnormal processing of the amyloid precursor protein and tau processing. In the quest for upstream drivers of sporadic, late-onset AD neurodegeneration, nerve growth factor (NGF) has a central role. Initially connected to AD on a purely correlative basis, because of its neurotrophic actions on basal forebrain cholinergic neurons, two independent lines of research, reviewed in this article, place alterations of NGF processing and signaling at the center stage of a new mechanism, leading to the activation of amyloidogenesis and tau processing. Thus, experimental studies on NGF deficit induced neurodegeneration in transgenic mice, as well as the mechanistic studies on the anti-amyloidogenic actions of NGF/TrkA signaling in primary neuronal cultures demonstrated a novel causal link between neurotrophic signaling deficits and Alzheimers neurodegeneration. Around these results, a new NGF hypothesis can be built, with neurotrophic deficits of various types representing an upstream driver of the core AD triad pathology. According to the new NGF hypothesis for AD, therapies aimed at reestablishing a correct homeostatic balance between ligands (and receptors) of the NGF pathway appear to have a clear and strong rationale, not just as long-term cholinergic neuroprotection, but also as a truly disease-modifying approach.

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