Molecular Neurobiology Unit

Santa Lucia di Serino, Italy

Molecular Neurobiology Unit

Santa Lucia di Serino, Italy
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Ferrucci M.,University of Pisa | Spalloni A.,Molecular Neurobiology Unit | Bartalucci A.,University of Pisa | Cantafora E.,University of Pisa | And 6 more authors.
Neurobiology of Disease | Year: 2010

Transgenic mice expressing the human superoxide dismutase 1 (SOD-1) mutant at position 93 (G93A) develop a phenotype resembling amyotrophic lateral sclerosis (ALS). In fact, G93A mice develop progressive motor deficits which finally lead to motor palsy and death. This is due to the progressive degeneration of motor neurons in the ventral horn of the spinal cord. Although a similar loss is reported for specific cranial motor nuclei, only a few studies so far investigated degeneration in a few brainstem nuclei. We recently reported that chronic lithium administration delays onset and duration of the disease, while reducing degeneration of spinal motor neuron. In the present study, we extended this investigation to all somatic motor nuclei of the brain stem in the G93A mice and we evaluated whether analogous protective effects induced by lithium in the spinal cord were present at the brain stem level. We found that all motor but the oculomotor nuclei were markedly degenerated in G93A mice, and chronic treatment with lithium significantly attenuated neurodegeneration in the trigeminal, facial, ambiguus, and hypoglossal nuclei. Moreover, in the hypoglossal nucleus, we found that recurrent collaterals were markedly lost in G93A mice while they were rescued by chronic lithium administration. © 2009 Elsevier Inc. All rights reserved.


Middei S.,CNR Institute of Neuroscience | Middei S.,Experimental Neurology Unit | Spalloni A.,Molecular Neurobiology Unit | Longone P.,Molecular Neurobiology Unit | And 6 more authors.
Learning and Memory | Year: 2012

The modulation of synaptic strength associated with learning is post-synaptically regulated by changes in density and shape of dendritic spines. The transcription factor CREB (cAMP response element binding protein) is required for memory formation and in vitro dendritic spine rearrangements, but its role in learning-induced remodeling of neurons remains elusive. Using transgenic mice conditionally expressing a dominant-negative CREB (CREBS133A: mCREB) mutant, we found that inhibiting CREB function does not alter spine density, spine morphology, and levels of polymerized actin in naive CA1 neurons. CREB inhibition, however, impaired contextual fear conditioning and produced a learning-induced collapse of spines associated with a blockade of learning-dependent increase in actin polymerization. Blocking mCREB expression with doxycycline rescued memory and restored a normal pattern of learning-induced spines, demonstrating that CREB controls structural adaptations of neurons selectively involved in memory formation. © 2012 Cold Spring Harbor Laboratory Press.


Ranno E.,CNR Institute of Neurological Sciences | Ranno E.,University of Catania | D'Antoni S.,CNR Institute of Neurological Sciences | Spatuzza M.,CNR Institute of Neurological Sciences | And 8 more authors.
Neurobiology of Disease | Year: 2014

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor neurons (MNs) and astrogliosis. Recent evidence suggests that factors secreted by activated astrocytes might contribute to degeneration of MNs. We focused on endothelin-1 (ET-1), a peptide which is strongly up-regulated in reactive astrocytes under different pathological conditions. We show that ET-1 is abundantly expressed by reactive astrocytes in the spinal cord of the SOD1-G93A mouse model and sporadic ALS patients. To test if ET-1 might play a role in degeneration of MNs, we investigated its effect on MN survival in an in vitro model of mixed rat spinal cord cultures (MSCs) enriched of astrocytes exhibiting a reactive phenotype. ET-1 exerted a toxic effect on MNs in a time- and concentration-dependent manner, with an exposure to 100-200nM ET-1 for 48h resulting in 40-50% MN cell death. Importantly, ET-1 did not induce MN degeneration when administered on cultures treated with AraC (5μM) or grown in a serum-free medium that did not favor astrocyte proliferation and reactivity. We found that both ETA and ETB receptors are enriched in astrocytes in MSCs. The ET-1 toxic effect was mimicked by ET-3 (100nM) and sarafotoxin S6c (10nM), two selective agonists of endothelin-B receptors, and was not additive with that of ET-3 suggesting the involvement of ETB receptors. Surprisingly, however, the ET-1 effect persisted in the presence of the ETB receptor antagonist BQ-788 (200nM-2μM) and was slightly reversed by the ETA receptor antagonist BQ-123 (2μM), suggesting an atypical pharmacological profile of the astrocytic receptors responsible for ET-1 toxicity. The ET-1 effect was not undone by the ionotropic glutamate receptor AMPA antagonist GYKI 52466 (20μM), indicating that it is not caused by an increased glutamate release. Conversely, a 48-hour ET-1 treatment increased MN cell death induced by acute exposure to AMPA (50μM), which is indicative of two distinct pathways leading to neuronal death.Altogether these results indicate that ET-1 exerts a toxic effect on cultured MNs through mechanisms mediated by reactive astrocytes and suggest that ET-1 may contribute to MN degeneration in ALS. Thus, a treatment aimed at lowering ET-1 levels or antagonizing its effect might be envisaged as a potential therapeutic strategy to slow down MN degeneration in this devastating disease. © 2014 Elsevier Inc.


Nutini M.,University of Rome Tor Vergata | Frazzini V.,Molecular Neurology Unit | Marini C.,Molecular Neurobiology Unit | Marini C.,Leibniz Institute for Neurobiology | And 5 more authors.
Neuropharmacology | Year: 2011

Zn 2+ is co-released at glutamatergic synapses throughout the central nervous system and acts as a neuromodulator for glutamatergic neurotransmission, as a key modulator of NMDA receptor functioning. Zn 2+ is also implicated in the neurotoxicity associated with several models of acute brain injury and neurodegeneration. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons in the spinal cord and cortex. In this study, we have investigated the modulatory role exerted by Zn 2+ in NMDA-mediated neurotoxicity in either near-pure or mixed cortical cultured neurons obtained from either mice over-expressing the G93A mutant form of Cu/Zn superoxide dismutase (SOD1) human gene, a gene linked to familial ALS, or wild type (WT) mice. To that aim, SOD1 G93A or WT cultures were exposed to either NMDA by itself or to Zn 2+ prior to a toxic challenge with NMDA, and neuronal loss evaluated 24 h later. While we failed to observe any significant difference between NMDA and Zn 2+/NMDA-mediated toxicity in mixed SOD1 G93A or WT cortical cultures, different vulnerability to these toxic paradigms was found in near-pure neuronal cultures. In the WT near-pure neuronal cultures, a brief exposure to sublethal concentrations of Zn 2+-enhanced NMDA receptor-mediated cell death, an effect that was far more pronounced in the SOD1 G93A cultures. This increased excitotoxicity in SOD1 G93A near-pure neuronal cultures appears to be mediated by a significant increase in NMDA-dependent rises of intraneuronal Ca 2+ levels as well as enhanced production of cytosolic reactive oxygen species, while the injurious process seems to be unrelated to activation of nNOS or ERK1/2 pathways. This article is part of a Special Issue entitled 'Trends in Neuropharmacology: In Memory of Erminio Costa'. © 2011 Elsevier Ltd. All rights reserved.


Spalloni A.,Molecular Neurobiology Unit | Longone P.,Molecular Neurobiology Unit
Neuroscience and Biobehavioral Reviews | Year: 2016

Amyotrophic lateral sclerosis (ALS) is now recognized as a multisystem disorder, in which the primary pathology is the degeneration of motor neurons, with cognitive and/or behavioral dysfunctions that constitutes the non-motor manifestations of ALS. The combination of clinical, neuroimaging, and neuropathological data, and detailed genetic studies suggest that ALS and frontotemporal dementia (FTD) might form part of a disease continuum, with pure ALS and pure FTD at the two extremes.Mutations in the superoxide dismutase 1 (SOD1) gene were the first genetic mutations linked to the insurgence of ALS. Since that discovery numerous animal models carrying SOD1 mutations have been created. Despite their limitations these animal models, particularly the mice, have broaden our knowledge on the system alterations occurring in the ALS spectrum of disorders.The present review aims at providing an overview of the data obtained with the SOD1 animal models first and foremost on the cortical and subcortical regions, the cortico-striatal and hippocampal synaptic plasticity, dendritic branching and glutamate receptors function. © 2015 Elsevier Ltd.


Origlia N.,CNR Institute of Neuroscience | Trabalza A.,University of Rome La Sapienza | Nutini M.,University of Rome Tor Vergata | Bernardi G.,University of Rome Tor Vergata | And 4 more authors.
Cerebral Cortex | Year: 2011

Although amyotrophic lateral sclerosis (ALS) has long been considered as a lower motor neuron (MN) disease, degeneration of upper MNs arising from a combination of mechanisms including insufficient growth factor signaling and enhanced extracellular glutamate levels is now well documented. The observation that these mechanisms are altered in presymptomatic superoxide dismutase (SOD1) mice, an ALS mouse model, suggests that defective primary motor cortex (M1) synaptic activity might precede the onset of motor disturbances. To examine this point, we assessed the composition of AMPAR and NMDAR subunits and of the alphaCa 2+/calmodulin-dependent kinase autophosphorylation at threonine-286 in the triton insoluble fraction from the M1 in postnatal P80-P85 SOD1 G93A and wild-type mice. We show that presymptomatic SOD1 G93A exhibit a selective decrease of NR2A subunit expression and of the alphaCa 2+/calmodulin-dependent kinase autophosphorylation at threonine-286 in the triton insoluble fraction of upper MNs synapses. These molecular alterations are associated with synaptic plasticity defects, and a reduction in upper MN dendritic outgrowth revealing that abnormal neuronal connectivity in the M1 region precedes the onset of motor symptoms. We suggest that the progressive disruption of M1 corticocortical connections resulting from the SOD1 G93A mutation might extend to adjacent regions and promote development of cognitive/dementia alterations frequently associated with ALS. © 2011 The Author. Published by Oxford University Press. All rights reserved.


Nutini M.,Molecular Neurobiology Unit | Nutini M.,University of Rome Tor Vergata | Spalloni A.,Molecular Neurobiology Unit | Florenzano F.,Molecular Neurobiology Unit | And 6 more authors.
Molecular and Cellular Neuroscience | Year: 2011

Amyotrophic lateral sclerosis (ALS) is an adult-onset disease characterized by the progressive degeneration of motoneurons (MNs). Altered electrical properties have been described in familial and sporadic ALS patients. Cortical and spinal neurons cultured from the mutant Cu,Zn superoxide dismutase 1 (SOD1G93A) mouse, a murine model of ALS, exhibit a marked increase in the persistent Na+ currents. Here, we investigated the effects of the SOD1G93A mutation on the expression of the voltage-gated Na+ channel alpha subunit SCN8A (Nav1.6) and the beta subunits SCN1B (beta1), SCN2B (beta2), and SCN3B (beta3) in MNs of the spinal cord in presymptomatic (P75) and symptomatic (P120) mice. We observed a significant increase, within lamina IX, of the beta3 transcript and protein expression. On the other hand, the beta1 transcript was significantly decreased, in the same area, at the symptomatic stage, while the beta2 transcript levels were unaltered. The SCN8A transcript was significantly decreased at P120 in the whole spinal cord. These data suggest that the SOD1G93A mutation alters voltage-gated Na+ channel subunit expression. Moreover, the increased expression of the beta3 subunit support the hypothesis that altered persistent Na+ currents contribute to the hyperexcitability observed in the ALS-affected MNs. © 2011 Elsevier Inc.


Di Michele F.,Experimental Neurology | Luchetti S.,Royal Netherlands Academy of Arts and science | Bernardi G.,Experimental Neurology | Bernardi G.,University of Rome Tor Vergata | And 2 more authors.
Frontiers in Neuroendocrinology | Year: 2013

Parkinson's disease (PD) is associated with a massive loss of dopaminergic cells in the substantia nigra leading to dopamine hypofunction and alteration of the basal ganglia circuitry. These neurons, are under the control, among others, of the excitatory glutamatergic and inhibitory γ-aminobutyric acid (GABA) systems. An imbalance between these systems may contribute to excitotoxicity and dopaminergic cell death. Neurosteroids, a group of steroid hormones synthesized in the brain, modulate the function of several neurotransmitter systems. The substantia nigra of the human brain expresses high concentrations of allopregnanolone (3α, 5αtetrahydroprogesterone), a neurosteroid that positively modulates the action of GABA at GABAA receptors and of 5α-dihydroprogesterone, a neurosteroid acting at the genomic level. This article reviews the roles of NS acting as neuroprotectants and as GABAA receptor agonists in the physiology and pathophysiology of the basal ganglia, their impact on dopaminergic cell activity and survival, and potential therapeutic application in PD. © 2013 Elsevier Inc.


Spalloni A.,Molecular Neurobiology Unit | Nutini M.,Molecular Neurobiology Unit | Longone P.,Molecular Neurobiology Unit
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2013

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease pathologically characterized by the massive loss of motor neurons in the spinal cord, brain stem and cerebral cortex. There is a consensus in the field that ALS is a multifactorial pathology and a number of possible mechanisms have been suggested. Among the proposed hypothesis, glutamate toxicity has been one of the most investigated. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor mediated cell death and impairment of the glutamate-transport system have been suggested to play a central role in the glutamate-mediated motor neuron degeneration. In this context, the role played by the N-methyl-d-aspartate (NMDA) receptor has received considerable less attention notwithstanding its high Ca2+ permeability, expression in motor neurons and its importance in excitotoxicity. This review overviews the critical role of NMDA-mediated toxicity in ALS, with a particular emphasis on the endogenous modulators of the NMDAR. © 2012 Elsevier B.V.


PubMed | Molecular Neurobiology Unit
Type: | Journal: Neuroscience and biobehavioral reviews | Year: 2016

Amyotrophic lateral sclerosis (ALS) is now recognized as a multisystem disorder, in which the primary pathology is the degeneration of motor neurons, with cognitive and/or behavioral dysfunctions that constitutes the non-motor manifestations of ALS. The combination of clinical, neuroimaging, and neuropathological data, and detailed genetic studies suggest that ALS and frontotemporal dementia (FTD) might form part of a disease continuum, with pure ALS and pure FTD at the two extremes. Mutations in the superoxide dismutase 1 (SOD1) gene were the first genetic mutations linked to the insurgence of ALS. Since that discovery numerous animal models carrying SOD1 mutations have been created. Despite their limitations these animal models, particularly the mice, have broaden our knowledge on the system alterations occurring in the ALS spectrum of disorders. The present review aims at providing an overview of the data obtained with the SOD1 animal models first and foremost on the cortical and subcortical regions, the cortico-striatal and hippocampal synaptic plasticity, dendritic branching and glutamate receptors function.

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