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A prominent feature of neurodegenerative diseases is synaptic dysfunction and spine loss as early signs of neurodegeneration. In this context, accumulation of misfolded proteins has been identified as one of the most common causes driving... more
A prominent feature of neurodegenerative diseases is synaptic dysfunction and spine loss as early signs of neurodegeneration. In this context, accumulation of misfolded proteins has been identified as one of the most common causes driving synaptic toxicity at excitatory glutamatergic synapses. In particular, a great effort has been placed on dissecting the interplay between the toxic deposition of misfolded proteins and synaptic defects, looking for a possible causal relationship between them. Several studies have demonstrated that misfolded proteins could directly exert negative effects on synaptic compartments, altering either the function or the composition of pre- and post-synaptic receptors. In this review, we focused on the physiopathological role of tau and α-synuclein at the level of postsynaptic glutamate receptors. Tau is a microtubule-associated protein mainly expressed by central nervous system neurons where it exerts several physiological functions. In some cases, it un...
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The interaction of Rabphilin-3A (Rph3A) with the NMDA receptor (NMDAR) in hippocampal neurons plays a pivotal role in the synaptic retention of this receptor. The formation of a Rph3A/NMDAR complex is needed for the induction of long-term... more
The interaction of Rabphilin-3A (Rph3A) with the NMDA receptor (NMDAR) in hippocampal neurons plays a pivotal role in the synaptic retention of this receptor. The formation of a Rph3A/NMDAR complex is needed for the induction of long-term potentiation and NMDAR-dependent hippocampal behaviors, such as spatial learning. Moreover, Rph3A can also interact with AMPA receptors (AMPARs) through the formation of a complex with myosin Va. Here, we used a confocal imaging approach to show that Rph3A overexpression in primary hippocampal neuronal cultures is sufficient to promote increased dendritic spine density. This morphological event is correlated with an increase in GluN2A-containing NMDARs at synaptic membranes and a decrease in the surface levels of GluA1-containing AMPARs. These molecular and morphological modifications of dendritic spines are sufficient to occlude the spine formation induced by long-term potentiation, but do not prevent the spine loss induced by long-term depression...
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Abstracts of the IX Congresso SindemItalian Association for the study of Dementia linked to the Italian Neurological Society (SIN)Firenze, Palazzo dei Congressi, Villa Vittoria March 13-15, 2014Comitato Scientifico: Vincenzo Bonavita,... more
Abstracts of the IX Congresso SindemItalian Association for the study of Dementia linked to the Italian Neurological Society (SIN)Firenze, Palazzo dei Congressi, Villa Vittoria March 13-15, 2014Comitato Scientifico: Vincenzo Bonavita, Alessandro Padovani, Amalia Bruni, Leonardo Pantoni, Carlo Caltagirone, Lucilla Parnetti, Francesca Clerici, Daniela Perani, Monica Di Luca, Sandro Sorbi, Gianluigi Forloni, Francesco Tagliavini, Giovanni Frisoni, Marilu Gorno Tempini, Claudio Mariani, Annalena Venneri, Massimo Musicco.
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Research Interests: Neuroscience, Cognitive Science, Animal Behavior, Long Term Potentiation, Biology, and 15 moreNeurotransmission, Medicine, Mice, Animals, Male, Neuronal Plasticity, Clinical Sciences, SYNAPSES, Metaplasticity, Maze Learning, Neurosciences, Cognition disorders, Amyloid Beta Precursor Protein, Hippocampal formation, and NMDA receptor
Research Interests: Pathology, Cognitive Science, MRI, Progressive Supranuclear Palsy, Medicine, and 15 moreCerebrospinal Fluid, Humans, Female, Male, Differential Diagnosis, Clinical Sciences, Aged, Middle Aged, Atrophy, Frontotemporal Dementia, Biological markers, Early Diagnosis, Neurosciences, Neuropsychological Tests, and Mesencephalon
A correct interplay between dopamine (DA) and glutamate is essential for corticostriatal synaptic plasticity and motor activity. In an experimental model of Parkinson's disease (PD) obtained in rats, the complete depletion of striatal... more
A correct interplay between dopamine (DA) and glutamate is essential for corticostriatal synaptic plasticity and motor activity. In an experimental model of Parkinson's disease (PD) obtained in rats, the complete depletion of striatal DA, mimicking advanced stages of the disease, results in the loss of both forms of striatal plasticity: long-term potentiation (LTP) and long-term depression (LTD). However, early PD stages are characterized by an incomplete reduction in striatal DA levels. The mechanism by which this incomplete reduction in DA level affects striatal synaptic plasticity and glutamatergic synapses is unknown. Here we present a model of early PD in which a partial denervation, causing mild motor deficits, selectively affects NMDA-dependent LTP but not LTD and dramatically alters NMDA receptor composition in the postsynaptic density. Our findings show that DA decrease influences corticostriatal synaptic plasticity depending on the level of depletion. The use of the TA...
Research Interests: Neuroscience, Chemistry, Electrophysiology, Long Term Potentiation, Biology, and 15 moreImmunohistochemistry, Confocal Microscopy, Medicine, Dopamine, Animals, Male, Neuronal Plasticity, Substantia nigra, Denervation, Rats, Metaplasticity, Excitatory Postsynaptic Potentials, NMDA receptor, Psychology and Cognitive Sciences, and Medical and Health Sciences
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ABSTRACT Here we summarise current knowledge about biological markers available for early Alzheimer Disease detection. In fact delineating disease process from “normal ageing” may be difficult in the very early stages; in later stages of... more
ABSTRACT Here we summarise current knowledge about biological markers available for early Alzheimer Disease detection. In fact delineating disease process from “normal ageing” may be difficult in the very early stages; in later stages of the disease distinguishing Dementia of Alzheimer Type from a number of neurodegenerative diseases associated with dementia may also be troublesome.
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Research Interests: Biochemistry, Mass Spectrometry, Biology, Neurochemistry, Medicine, and 15 moreCerebral Cortex, Animals, Phosphorylation, Immunoprecipitation, Endogenous Growth, Kinase, Cattle, Chickens, Amino Acid Sequence, Axons, Neurosciences, Molecular Sequence Data, Geneeskunde, Protein Kinase C, and In Vitro Techniques
Research Interests: Long Term Potentiation, Biology, Membrane Proteins, Cell Biology, Medicine, and 15 moreHippocampus, Cercopithecus aethiops, Humans, Adam, Mice, Endocytosis, Animals, Amino Acid Sequence, Alzheimer Disease, Clinical Investigation, Disintegrin, Amyloid Beta Precursor Protein, Molecular Sequence Data, Cell Membrane, and Medical and Health Sciences
Neuronal ceroid lipofuscinoses (NCLs) are a group of hereditary childhood diseases characterized mainly by lipopigment accumulation and a multisystemic pattern of symptoms including mental retardation, seizures, motor impairment, and... more
Neuronal ceroid lipofuscinoses (NCLs) are a group of hereditary childhood diseases characterized mainly by lipopigment accumulation and a multisystemic pattern of symptoms including mental retardation, seizures, motor impairment, and blindness. The mnd mouse, carrying a mutation in the Cln8 gene, has been proposed as a model of epilepsy with mental retardation (EPMR, ornorthern epilepsy). We recently showed neuronal hyperexcitability and seizure hypersusceptibility in mnd mice. To elucidate the cellular mechanisms related to hippocampal hyperexcitability, the glutamatergic transmission and the expression of postsynaptic glutamate receptors were investigated in hippocampus. A significant increase in either spontaneous or KCl-stimulated overflow of [(3) H]D-aspartate was found in mnd mice compared with controls. This increase was maintained after DL-threo-β-benzyloxyaspartic acid (TBOA) treatment, suggesting a nonrelevant role for transporter-mediated release and supporting the involv...
Research Interests: Neuroscience, Psychology, Epilepsy, Biology, Membrane Proteins, and 15 moreMedicine, Hippocampus, Mice, Glutamate receptors, Animals, Male, Astrocytes, Analysis of Variance, Glial Fibrillary Acidic Protein, SYNAPTOSOMES, Neurosciences, Potassium Chloride, Gene Expression Regulation, Glutamate Receptor, and NMDA receptor
The neuropeptide pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) has been implicated in the induction of synaptic plasticity at the excitatory glutamatergic synapse. In particular, recent studies have shown that it is... more
The neuropeptide pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) has been implicated in the induction of synaptic plasticity at the excitatory glutamatergic synapse. In particular, recent studies have shown that it is involved in the regulation of NMDA and AMPA receptor activation. Here we demonstrate the effect of PACAP38 on the modulation of dendritic spine morphology through ADAM10/N-Cadherin/AMPA receptor signaling pathway. Treatment of primary hippocampal neurons with PACAP38 induces an accumulation of ADAM10 at the postsynaptic membrane. This event leads to a significant decrease of dendritic spine head width and to a concomitant reduction of GluR1 co-localization with postsynaptic markers. PACAP38-induced effect on dendritic spine head width is prevented by either treatment with ADAM10 specific inhibitor or transfection of a cleavage-defective N-Cadherin construct, mutated in the ADAM10 cleavage site. Overall, our findings reveal for the first time that PACAP3...
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Research Interests: Biology, Medicine, Dopamine, Striatum, Animals, and 15 moreMale, Phosphorylation, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis, Antagonist, European, In Vivo, Rats, Molecular weight, Protein Phosphorylation, Sch, Agonist, dopaminergic, Corpus striatum, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
Research Interests: Neuroscience, Chemistry, Medicine, Neuroprotection, Hippocampus, and 15 moreAnimals, Rats, Time Factors, Rat, SYNAPSES, Clinical Study, Glutamic Acid, Postsynaptic Density, Neuroprotective Agents, Glutamate Receptor, Excitatory Postsynaptic Potentials, NMDA receptor, Indans, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
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We have previously shown that protein kinase C (PKC) activity is up‐regulated in nerve terminals of animals that have been subjected to targeted cellular ablation of cortical and hippocampal neurons by treatment with methylazoxymethanol... more
We have previously shown that protein kinase C (PKC) activity is up‐regulated in nerve terminals of animals that have been subjected to targeted cellular ablation of cortical and hippocampal neurons by treatment with methylazoxymethanol (MAM), which results in impaired long‐term potentiation (LTP) and cognitive deficit. In this study we investigated the consequences of increased membrane‐bound PKC in the regulation of release of glutamate, the major excitatory transmitter involved in LTP. We show that nerve terminals of MAM‐treated rats show higher PKC activity, as monitored by the in situ phosphorylation of B‐50/GAP‐43, in both basal and phorbol ester‐stimulated conditions. In these animals, hippocampal nerve endings release a greater amount of glutamate than those of controls, both in basal conditions and when synaptosomes are stimulated with KCI or 3,4–diaminopyridine. The potentiation observed in MAM‐treated rats was counteracted by the PKC blocker H‐7 and the clostridial tetanu...
Research Interests: Psychology, Cognitive Science, Long Term Potentiation, Biology, Medicine, and 15 moreSynaptic Plasticity, Hippocampus, Pregnancy, Female, Animals, European, Rats, Neurosciences, Glutamic Acid, Glutamate Receptor, Hippocampal formation, Depolarization, Glutamate release, Geneeskunde, and Protein Kinase C
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Background: The alpha-secretase is a proteolytic activity, which cleaves within the amyloid ß (Aß) sequence and, thus, prevents Aß generation. The identity of alpha-secretase is unknown, but several proteases, including ‘‘a disintegrin... more
Background: The alpha-secretase is a proteolytic activity, which cleaves within the amyloid ß (Aß) sequence and, thus, prevents Aß generation. The identity of alpha-secretase is unknown, but several proteases, including ‘‘a disintegrin and metalloproteases’’, have been proposed to be candidate alpha-secretases. Methods: To systematically characterize proteases with alpha-secretase activity, we first mapped the alpha-secretase cleavage sites within the Aß domain of APP and then screened for proteases cleaving at these sites. Results: We found that the main cleavage site is between amino acids 16 and 17 of the Aß sequence, which we refer to as major alpha-secretase cleavage site. Additional cleavage sites were identified at nearby peptide bonds, but only represent a smaller amount of total APP alphasecretase shedding. In order to selectively detect the secreted APP ending at the major alpha-secretase cleavage site, we generated a monoclonal antibody detecting the neoepitope arising through this cleavage. Next, we individually knocked-down different proteases and evaluated their contribution to the major alpha-secretase cleavage site of APP in neuronal cells. Surprisingly, we found that the knock-down of a single metalloprotease was sufficient to completely suppress APP shedding at the major cleavage site. This reveals that other proteases were not able to compensate for this loss of cleavage. Conclusions: In summary, our data show that a) distinct proteases contribute to total alpha-secretase cleavage of APP, but that b) only a single metalloprotease seems to mediate APP shedding at the major cleavage site.
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Recently, the striatum has been implicated in the spread of epileptic seizures. As the absence of functional scaffolding protein Bassoon in mutant mice is associated with the development of pronounced spontaneous seizures, we utilized... more
Recently, the striatum has been implicated in the spread of epileptic seizures. As the absence of functional scaffolding protein Bassoon in mutant mice is associated with the development of pronounced spontaneous seizures, we utilized this new genetic model of epilepsy to investigate seizure‐induced changes in striatal synaptic plasticity. Mutant mice showed reduced long‐term potentiation in striatal spiny neurons, associated with an altered N‐methyl‐d‐aspartate (NMDA) receptor subunit distribution, whereas GABAergic fast‐spiking (FS) interneurons showed NMDA‐dependent short‐term potentiation that was absent in wild‐type animals. Alterations in the dendritic morphology of spiny neurons and in the number of FS interneurons were also observed. Early antiepileptic treatment with valproic acid reduced epileptic attacks and mortality, rescuing physiological striatal synaptic plasticity and NMDA receptor subunit composition. However, morphological alterations were not affected by antiepil...
Research Interests: Neuroscience, Psychology, Cognitive Science, Long Term Potentiation, Epilepsy, and 15 moreBiology, Immunohistochemistry, Medicine, Striatum, Mice, Animals, Neuronal Plasticity, European, Fluorescent Antibody Technique, Neurosciences, Postsynaptic Density, Glutamate Receptor, Corpus striatum, NMDA receptor, and Gabaergic
Many neurological disorders accompanied by cognitive deficits exhibit abnormal synaptic function. This emerging concept is exemplified by Alzheimer's disease. According to the amyloid hypothesis, Alzheimer's disease is thought to... more
Many neurological disorders accompanied by cognitive deficits exhibit abnormal synaptic function. This emerging concept is exemplified by Alzheimer's disease. According to the amyloid hypothesis, Alzheimer's disease is thought to be caused by the progressive accumulation and deposition of neurotoxic Amyloid beta-peptide in amyloid plaques and aggregates in brain. Now new theories are emerging associating synaptic and neuronal loss to Amyloid beta monomers and Amyloid beta oligomers. In particular, Amyloid beta oligomers have been described as the earliest effectors to adversely affect synaptic structure and plasticity. In this way, they compromise aspects of learning and memory, including long-term potentiation. Local inflammatory changes, neurofibrillary degeneration, and neurotransmitter deficits all contribute to the memory impairment, but available evidence suggests that these alterations develop as a consequence of early Amyloid beta accumulation. Even more recently, di...
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Generation of Amyloid peptide (Abeta) is at the beginning of a cascade that leads to Alzheimer's disease. Currenty, the mechanisms of Abeta generation and Abeta prevention are subject of intensive research. Amyloid precursor protein... more
Generation of Amyloid peptide (Abeta) is at the beginning of a cascade that leads to Alzheimer's disease. Currenty, the mechanisms of Abeta generation and Abeta prevention are subject of intensive research. Amyloid precursor protein (APP), as well as beta- and gamma-secretases are the principal players involved in Abeta production, while alpha-secretase cleavage on APP prevents Abeta deposition. Inhibitors or modulators that target beta- and gamma-secretases as well as alpha-secretase activators are promising candidates for treatment of Alzheimer's disease. A deep knowledge of the secretases is required to develop disease modifying drugs that target them. The most challenging quest is to translate the growing knowledge about the cell biology of secretases and their mechanisms of action into effective therapeutics. Here, we review the main features of the secretases.
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A correct clinical diagnosis in the early stage of Alzheimer Disease (AD) is mandatory given the current available treatment with acetylcholine esterase inhibitors. Moreover, a early to preclinical diagnosis would allow to identify... more
A correct clinical diagnosis in the early stage of Alzheimer Disease (AD) is mandatory given the current available treatment with acetylcholine esterase inhibitors. Moreover, a early to preclinical diagnosis would allow to identify patients eligible for future disease-modifying therapies. In the last ten years, we have focused our attention on peripheral markers, evaluating the role of platelet Amyloid Precursor Protein (APP) forms as a reliable tool for AD diagnosis since preclinical stages. APP is the key player in AD pathogenesis, and platelets contain all the enzymatic machinery to its processing, thus being the ideal candidate where to study AD pathogenetic mechanisms. In this review, we summarise the published data regarding the usefulness of platelet APP form ratio in the diagnosis of early AD. Approaches combining APP form ratio along with neuroimaging markers show the promise to accurately identify AD, even in the pre-symptomatic stage.
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Generation of amyloid peptide (Aβ) is at the beginning of a cascade that leads to Alzheimer's disease (AD). Amyloid precursor protein (APP), as well as β- and γ-secretases, is the principal player involved in Aβ production, while... more
Generation of amyloid peptide (Aβ) is at the beginning of a cascade that leads to Alzheimer's disease (AD). Amyloid precursor protein (APP), as well as β- and γ-secretases, is the principal player involved in Aβ production, while α-secretase cleavage on APP prevents Aβ deposition. Recent studies suggested that soluble assembly states of Aβ peptides can cause cognitive problems by disrupting synaptic function in the absence of significant neurodegeneration. Therefore, current research investigates the relative importance of these various soluble Aβ assemblies in causing synaptic dysfunction and cognitive deficits. Several Aβ oligomers targets and cellular mechanisms responsible of Aβ-induced synaptic failure have been identified. The first and most important mechanism impugns a toxic gain of function for Aβ which results due to self-association and attainment of new structures capable of novel interactions that lead to impaired plasticity. Other scenarios predicate that Aβ has a ...
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Zinc (Zn(2+) ) is believed to play a relevant role in the physiology and pathophysiology of the brain. Hence, Zn(2+) homeostasis is critical and involves different classes of molecules, including Zn(2+) transporters. The ubiquitous Zn(2+)... more
Zinc (Zn(2+) ) is believed to play a relevant role in the physiology and pathophysiology of the brain. Hence, Zn(2+) homeostasis is critical and involves different classes of molecules, including Zn(2+) transporters. The ubiquitous Zn(2+) transporter-1 (ZNT-1) is a transmembrane protein that pumps cytosolic Zn(2+) to the extracellular space, but its function in the central nervous system is not fully understood. Here, we show that ZNT-1 interacts with GluN2A-containing NMDA receptors, suggesting a role for this transporter at the excitatory glutamatergic synapse. First, we found that ZNT-1 is highly expressed at the hippocampal postsynaptic density (PSD) where NMDA receptors are enriched. Two-hybrid screening, coimmunoprecipitation experiments and clustering assay in COS-7 cells demonstrated that ZNT-1 specifically binds the GluN2A subunit of the NMDA receptor. GluN2A deletion mutants and pull-down assays indicated GluN2A(1390-1464) domain as necessary for the binding to ZNT-1. Most importantly, ZNT-1/GluN2A complex was proved to be dynamic, since it was regulated by induction of synaptic plasticity. Finally, modulation of ZNT-1 expression in hippocampal neurons determined a significant change in dendritic spine morphology, PSD-95 clusters and GluN2A surface levels, supporting the involvement of ZNT-1 in the dynamics of excitatory PSD. Zn(2+) transporter-1 (ZNT-1) pumps cytosolic Zn(2+) to the extracellular space, but its function in the central nervous system is not fully understood. We show that ZNT-1 interacts with GluN2A-containing NMDA receptors at the glutamatergic synapse. Most importantly, ZNT-1/GluN2A complex is regulated by induction of synaptic plasticity. Modulation of ZNT-1 expression in hippocampal neurons determined a shrinkage of dendritic spines and a reduction of GluN2A surface levels supporting the involvement of ZNT-1 in the dynamics of the excitatory synapse.
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Research Interests: Genetics, Cognitive Science, Dementia, Memory, Humans, and 17 moreGlucose Metabolism, Brain Ischemia, Risk factors, Aged, Middle Aged, Genotype, Single Photon Emission Computed Tomography, Adult, Long Term Memory, Brain Structure, Risk Factors, Parahippocampal Gyrus, Brain Function, Clinical Presentation, Cross Sectional Studies, Alzheimer Disease, and Neurosciences
Frontotemporal lobar degeneration (FTLD) refers to heterogeneous clinical and biological conditions. In FTLD, cerebrospinal fluid (CSF) tau levels have been reported highly variable. The aim of the present study was to evaluate whether... more
Frontotemporal lobar degeneration (FTLD) refers to heterogeneous clinical and biological conditions. In FTLD, cerebrospinal fluid (CSF) tau levels have been reported highly variable. The aim of the present study was to evaluate whether CSF tau might be the hallmark of a distinct FTLD phenotype. Fifty-five FTLD patients, who underwent CSF analysis, were considered in the present study. In each patient, a wide standardized neuropsychological evaluation, and CSF tau, phospho-tau, and amyloid-β (Aβ) dosages were performed. Each patient was followed-up to five years, and outcomes carefully recorded. In a subgroup of patients (n = 24), magnetic resonance imaging scanning was performed, by using voxel-based morphometry, for grey matter investigation. The higher the CSF tau levels, the worse the neuropsychological and neuroimaging pattern, mainly characterized by greater language disturbances and left temporal grey matter loss. The same pattern, even if less significant, was associated with CSF phospho-tau, while CSF Aβ levels did not play any influence on FTLD phenotype. FTLD patients with high CSF tau showed poor prognosis compared to those with low CSF tau (p = 0.031). In FTLD, CSF tau levels might be considered a marker of neurodegeneration, associated with a specific clinical and neuroimaging picture, and significantly related to poor outcome. Further studies aimed at defining the biological underpinnings of these findings are warranted.
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N-methyl-D-aspartate (NMDA) receptors have been implicated as a mediator of neuronal injury associated with many neurological disorders including ischemia, epilepsy, brain trauma, dementia and neurodegenerative disorders such as... more
N-methyl-D-aspartate (NMDA) receptors have been implicated as a mediator of neuronal injury associated with many neurological disorders including ischemia, epilepsy, brain trauma, dementia and neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease. To this, non-selective NMDA receptor antagonists have been tried and have been shown to be effective in many experimental animal models of disease, and some of these compounds have moved into clinical trials. However, the initial enthusiasm for this approach has waned, because the therapeutic index for most NMDA antagonists is quite poor, with significant adverse effects at clinically effective doses, thus limiting their utility. More recently, the concept that the exact pathways downstream NMDA receptor activation could represent a key variable element among neurological disorders has been put forward. In particular, variations in NMDA receptor subunit composition could be important in different disorders, both in the pathophysiological mechanisms of cell death and in the application of specific symptomatic therapies. As to PD, NMDA receptor complex has been shown to be altered in experimental models of parkinsonism and in PD in humans. Further, it has become increasingly evident that the NMDA receptor complex is intimately involved in the regulation of corticostriatal long-term potentiation, which is altered in experimental parkinsonism. The following sections will examine the modifications of specific NMDA receptor subunits as well as post-synaptic associated signalling complex including kinases and scaffolding proteins in experimental parkinsonism. These findings may allow the identification of specific molecular targets whose pharmacological or genetic manipulation might lead to innovative therapies for PD.
Research Interests: Genetics, Cognitive Science, Long Term Potentiation, Clinical Trial, Signal Transduction, and 15 moreMacaca, Humans, Mice, Animals, Cell Death, Neuronal Plasticity, Animal Model, Rats, SYNAPSES, Nervous System, Effective Dose, Neurosciences, Parkinson Disease, Glutamate Receptor, and Experimental Model
Pharmacological blockade of NR2B-containing N-methyl-d-aspartate receptors (NMDARs) during epileptogenesis reduces neurodegeneration provoked in the rodent hippocampus by status epilepticus. The functional consequences of NMDAR activation... more
Pharmacological blockade of NR2B-containing N-methyl-d-aspartate receptors (NMDARs) during epileptogenesis reduces neurodegeneration provoked in the rodent hippocampus by status epilepticus. The functional consequences of NMDAR activation are crucially influenced by their synaptic vs extrasynaptic localization, and both NMDAR function and localization are dependent on the presence of the NR2B subunit and its phosphorylation state. We investigated whether changes in NR2B subunit phosphorylation, and alterations in its neuronal membrane localization and cellular expression occur during epileptogenesis, and if these changes are involved in neuronal cell loss. We also explored NR2B subunit changes both in the acute phase of status epilepticus and in the chronic phase of spontaneous seizures which encompass the epileptogenesis phase. Levels of Tyr1472 phosphorylated NR2B subunit decreased in the post-synaptic membranes from rat hippocampus during epileptogenesis induced by electrical status epilepticus. This effect was concomitant with a reduced interaction between NR2B and post-synaptic density (PSD)-95 protein, and was associated with decreased CREB phosphorylation. This evidence suggests an extra-synaptic localization of NR2B subunit in epileptogenesis. Accordingly, electron microscopy showed increased NR2B both in extra-synaptic and pre-synaptic neuronal compartments, and a concomitant decrease of this subunit in PSD, thus indicating a shift in NR2B membrane localization. De novo expression of NR2B in activated astrocytes was also found in epileptogenesis indicating ectopic receptor expression in glia. The NR2B phosphorylation changes detected at completion of status epilepticus, and interictally in the chronic phase of spontaneous seizures, are predictive of receptor translocation from synaptic to extrasynaptic sites. Pharmacological blockade of NR2B-containing NMDARs by ifenprodil administration during epileptogenesis significantly reduced pyramidal cell loss in the hippocampus, showing that the observed post-translational and cellular changes of NR2B subunit contribute to excitotoxicity. Therefore, pharmacological targeting of misplaced NR2B-containing NMDARs, or prevention of these NMDAR changes, should be considered to block excitotoxicity which develops after various pro-epileptogenic brain injuries.
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ABSTRACT In view of the important role of PKC in synaptic plasticity we have investigated the ability of Nicergoline to affect translocation of PKC isoforms in synaptosomes obtained from distinct brain areas. In isolated synaptosomes... more
ABSTRACT In view of the important role of PKC in synaptic plasticity we have investigated the ability of Nicergoline to affect translocation of PKC isoforms in synaptosomes obtained from distinct brain areas. In isolated synaptosomes obtained from rat hippocampus and striatum, nicergoline was able to induce in a concentration dependent fashion the translocation of the Ca++-dependent PKC isozymes α and β, but not of the Ca++independent ϵ. The effect is confined to hippocampus and striatum. MDL, the major nicergoline metabolite, is more potent in modulating PKC activity in all the brain areas evaluated. These data suggest that PKC may represent an pharmacological target at presynaptic level for nicergoline and its derivates.