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Lucia Caffino - One of the best experts on this subject based on the ideXlab platform.

  • activity based anorexia dynamically dysregulates the Glutamatergic Synapse in the nucleus accumbens of female adolescent rats
    Nutrients, 2020
    Co-Authors: Francesca Mottarlini, Fabio Fumagalli, Giorgia Bottan, Benedetta Tarenzi, Alessandra Colciago, Lucia Caffino
    Abstract:

    Intense physical activity and dieting are core symptoms of anorexia nervosa (AN). Their combination evolves into compulsivity, leading the patient into an out-of-control spiral. AN patients exhibit an altered activation of nucleus accumbens (NAc), revealing a dysfunctional mesocorticolimbic reward circuitry in AN. Since evidence exists that a dysregulation of the glutamate system in the NAc influences reward and taking advantage of the activity-based anorexia (ABA) rat model, which closely mimics the hallmarks of AN, we investigated the involvement of the Glutamatergic signaling in the NAc in this experimental model. We here demonstrate that food restriction causes hyperactive and compulsive behavior in rodents, inducing an escalation of physical activity, which results in dramatic weight loss. Analysis of the glutamate system revealed that, in the acute phase of the pathology, ABA rats increased the membrane expression of GluA1 AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunits together with its scaffolding protein SAP97. Recovery of body weight reduced GluN2A/2B balance together with the expression of their specific scaffolding proteins, thus suggesting persistent maladaptive neurotransmission. Taken together, AMPA and NMDA (N-methyl-D-aspartate) receptor subunit reorganization may play a role in the motivational mechanisms underlying AN.

  • lsd1 is an environmental stress sensitive negative modulator of the Glutamatergic Synapse
    Neurobiology of Stress, 2020
    Co-Authors: Alessandra Longaretti, Lucia Caffino, Chiara Forastieri, Emanuela Toffolo, Andrea Locarno, I Miseviciūtė, E Marchesi, M Battistin, Luisa Ponzoni, L Madaschi
    Abstract:

    Abstract Along with neuronal mechanisms devoted to memory consolidation –including long term potentiation of synaptic strength as prominent electrophysiological correlate, and inherent dendritic spines stabilization as structural counterpart– negative control of memory formation and synaptic plasticity has been described at the molecular and behavioral level. Within this work, we report a role for the epigenetic corepressor Lysine Specific Demethylase 1 (LSD1) as a negative neuroplastic factor whose stress-enhanced activity may participate in coping with adverse experiences. Constitutively increasing LSD1 activity via knocking out its dominant negative splicing isoform neuroLSD1 (neuroLSD1KO mice), we observed extensive structural, functional and behavioral signs of excitatory decay, including disrupted memory consolidation. A similar LSD1 increase, obtained with acute antisense oligonucleotide-mediated neuroLSD1 splicing knock down in primary neuronal cultures, dampens spontaneous Glutamatergic transmission, reducing mEPSCs. Remarkably, LSD1 physiological increase occurs in response to psychosocial stress-induced Glutamatergic signaling. Since this mechanism entails neuroLSD1 splicing downregulation, we conclude that LSD1/neuroLSD1 ratio modulation in the hippocampus is instrumental to a negative homeostatic feedback, restraining Glutamatergic neuroplasticity in response to glutamate. The active process of forgetting provides memories with salience. With our work, we propose that softening memory traces of adversities could further represent a stress-coping process in which LSD1/neuroLSD1 ratio modulation may help preserving healthy emotional references.

  • stress rapidly dysregulates the Glutamatergic Synapse in the prefrontal cortex of cocaine withdrawn adolescent rats
    Addiction Biology, 2015
    Co-Authors: Lucia Caffino, Francesca Calabrese, Giuseppe Giannotti, Alessandro Barbon, Michel M. M. Verheij, Giorgio Racagni, Fabio Fumagalli
    Abstract:

    Although several lines of evidence have shown that chronic cocaine use is associated with stress system dysregulation, the underlying neurochemical mechanisms are still elusive. To investigate whether the rapid stress-induced response of the Glutamatergic Synapse was influenced by a previous history of cocaine, rats were exposed to repeated cocaine injections during adolescence [from postnatal day (PND) 28–42], subjected to a single swim stress (5 minutes) three days later (PND 45) and sacrificed 15 minutes after the end of this stressor. Critical determinants of Glutamatergic homeostasis were measured in the medial prefrontal cortex (mPFC) whereas circulating corticosterone levels were measured in the plasma. Exposure to stress in saline-treated animals did not show changes in the crucial determinants of the Glutamatergic Synapse. Conversely, in cocaine-treated animals, stress dynamically altered the Glutamatergic Synapse by: (1) enhancing the presynaptic vesicular mediators of glutamate release; (2) reducing the transporters responsible for glutamate clearance; (3) increasing the postsynaptic responsiveness of the N-methyl-D-aspartate subunit GluN1; and (4) causing hyperresponsive spines as evidenced by increased activation of the postsynaptic cdc42-Pak pathway. These findings indicate that exposure to cocaine during adolescence sensitizes mPFC Glutamatergic Synapses to stress. It is suggested that changes in Glutamatergic signaling may contribute to the increased sensitivity to stress observed in cocaine users. Moreover, Glutamatergic processes may play an important role in stress-induced reinstatement of cocaine seeking.

  • Stress rapidly dysregulates the Glutamatergic Synapse in the prefrontal cortex of cocaine‐withdrawn adolescent rats
    Addiction biology, 2013
    Co-Authors: Lucia Caffino, Francesca Calabrese, Giuseppe Giannotti, Alessandro Barbon, Michel M. M. Verheij, Giorgio Racagni, Fabio Fumagalli
    Abstract:

    Although several lines of evidence have shown that chronic cocaine use is associated with stress system dysregulation, the underlying neurochemical mechanisms are still elusive. To investigate whether the rapid stress-induced response of the Glutamatergic Synapse was influenced by a previous history of cocaine, rats were exposed to repeated cocaine injections during adolescence [from postnatal day (PND) 28–42], subjected to a single swim stress (5 minutes) three days later (PND 45) and sacrificed 15 minutes after the end of this stressor. Critical determinants of Glutamatergic homeostasis were measured in the medial prefrontal cortex (mPFC) whereas circulating corticosterone levels were measured in the plasma. Exposure to stress in saline-treated animals did not show changes in the crucial determinants of the Glutamatergic Synapse. Conversely, in cocaine-treated animals, stress dynamically altered the Glutamatergic Synapse by: (1) enhancing the presynaptic vesicular mediators of glutamate release; (2) reducing the transporters responsible for glutamate clearance; (3) increasing the postsynaptic responsiveness of the N-methyl-D-aspartate subunit GluN1; and (4) causing hyperresponsive spines as evidenced by increased activation of the postsynaptic cdc42-Pak pathway. These findings indicate that exposure to cocaine during adolescence sensitizes mPFC Glutamatergic Synapses to stress. It is suggested that changes in Glutamatergic signaling may contribute to the increased sensitivity to stress observed in cocaine users. Moreover, Glutamatergic processes may play an important role in stress-induced reinstatement of cocaine seeking.

Fabio Fumagalli - One of the best experts on this subject based on the ideXlab platform.

  • activity based anorexia dynamically dysregulates the Glutamatergic Synapse in the nucleus accumbens of female adolescent rats
    Nutrients, 2020
    Co-Authors: Francesca Mottarlini, Fabio Fumagalli, Giorgia Bottan, Benedetta Tarenzi, Alessandra Colciago, Lucia Caffino
    Abstract:

    Intense physical activity and dieting are core symptoms of anorexia nervosa (AN). Their combination evolves into compulsivity, leading the patient into an out-of-control spiral. AN patients exhibit an altered activation of nucleus accumbens (NAc), revealing a dysfunctional mesocorticolimbic reward circuitry in AN. Since evidence exists that a dysregulation of the glutamate system in the NAc influences reward and taking advantage of the activity-based anorexia (ABA) rat model, which closely mimics the hallmarks of AN, we investigated the involvement of the Glutamatergic signaling in the NAc in this experimental model. We here demonstrate that food restriction causes hyperactive and compulsive behavior in rodents, inducing an escalation of physical activity, which results in dramatic weight loss. Analysis of the glutamate system revealed that, in the acute phase of the pathology, ABA rats increased the membrane expression of GluA1 AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunits together with its scaffolding protein SAP97. Recovery of body weight reduced GluN2A/2B balance together with the expression of their specific scaffolding proteins, thus suggesting persistent maladaptive neurotransmission. Taken together, AMPA and NMDA (N-methyl-D-aspartate) receptor subunit reorganization may play a role in the motivational mechanisms underlying AN.

  • stress rapidly dysregulates the Glutamatergic Synapse in the prefrontal cortex of cocaine withdrawn adolescent rats
    Addiction Biology, 2015
    Co-Authors: Lucia Caffino, Francesca Calabrese, Giuseppe Giannotti, Alessandro Barbon, Michel M. M. Verheij, Giorgio Racagni, Fabio Fumagalli
    Abstract:

    Although several lines of evidence have shown that chronic cocaine use is associated with stress system dysregulation, the underlying neurochemical mechanisms are still elusive. To investigate whether the rapid stress-induced response of the Glutamatergic Synapse was influenced by a previous history of cocaine, rats were exposed to repeated cocaine injections during adolescence [from postnatal day (PND) 28–42], subjected to a single swim stress (5 minutes) three days later (PND 45) and sacrificed 15 minutes after the end of this stressor. Critical determinants of Glutamatergic homeostasis were measured in the medial prefrontal cortex (mPFC) whereas circulating corticosterone levels were measured in the plasma. Exposure to stress in saline-treated animals did not show changes in the crucial determinants of the Glutamatergic Synapse. Conversely, in cocaine-treated animals, stress dynamically altered the Glutamatergic Synapse by: (1) enhancing the presynaptic vesicular mediators of glutamate release; (2) reducing the transporters responsible for glutamate clearance; (3) increasing the postsynaptic responsiveness of the N-methyl-D-aspartate subunit GluN1; and (4) causing hyperresponsive spines as evidenced by increased activation of the postsynaptic cdc42-Pak pathway. These findings indicate that exposure to cocaine during adolescence sensitizes mPFC Glutamatergic Synapses to stress. It is suggested that changes in Glutamatergic signaling may contribute to the increased sensitivity to stress observed in cocaine users. Moreover, Glutamatergic processes may play an important role in stress-induced reinstatement of cocaine seeking.

  • Stress rapidly dysregulates the Glutamatergic Synapse in the prefrontal cortex of cocaine‐withdrawn adolescent rats
    Addiction biology, 2013
    Co-Authors: Lucia Caffino, Francesca Calabrese, Giuseppe Giannotti, Alessandro Barbon, Michel M. M. Verheij, Giorgio Racagni, Fabio Fumagalli
    Abstract:

    Although several lines of evidence have shown that chronic cocaine use is associated with stress system dysregulation, the underlying neurochemical mechanisms are still elusive. To investigate whether the rapid stress-induced response of the Glutamatergic Synapse was influenced by a previous history of cocaine, rats were exposed to repeated cocaine injections during adolescence [from postnatal day (PND) 28–42], subjected to a single swim stress (5 minutes) three days later (PND 45) and sacrificed 15 minutes after the end of this stressor. Critical determinants of Glutamatergic homeostasis were measured in the medial prefrontal cortex (mPFC) whereas circulating corticosterone levels were measured in the plasma. Exposure to stress in saline-treated animals did not show changes in the crucial determinants of the Glutamatergic Synapse. Conversely, in cocaine-treated animals, stress dynamically altered the Glutamatergic Synapse by: (1) enhancing the presynaptic vesicular mediators of glutamate release; (2) reducing the transporters responsible for glutamate clearance; (3) increasing the postsynaptic responsiveness of the N-methyl-D-aspartate subunit GluN1; and (4) causing hyperresponsive spines as evidenced by increased activation of the postsynaptic cdc42-Pak pathway. These findings indicate that exposure to cocaine during adolescence sensitizes mPFC Glutamatergic Synapses to stress. It is suggested that changes in Glutamatergic signaling may contribute to the increased sensitivity to stress observed in cocaine users. Moreover, Glutamatergic processes may play an important role in stress-induced reinstatement of cocaine seeking.

Fabrizio Gardoni - One of the best experts on this subject based on the ideXlab platform.

  • postsynaptic density membrane associated guanylate kinase proteins psd maguks and their role in cns disorders
    Neuroscience, 2009
    Co-Authors: Fabrizio Gardoni, Elena Marcello, M Di Luca
    Abstract:

    Membrane associated guanylate kinase proteins (MAGUKs) play a key role in the regulation of the intracellular trafficking and synaptic localization of ionotropic glutamate receptors. In particular, the postsynaptic density-95-like subfamily of MAGUKs (PSD-MAGUKs) organizes ionotropic glutamate receptors and their associated signaling proteins in the postsynaptic density of the excitatory Synapse regulating the strength of synaptic activity. Several recent observations clearly put forward the idea that alterations of PSD-MAGUK protein function such as alterations of PSD-MAGUK protein interaction with N-methyl-D-aspartate (NMDA) receptors regulatory subunits are common events in several CNS disorders. With this view, a better knowledge and understanding of PSD-MAGUK function as well as of the molecular events regulating PSD-MAGUK-mediated interactions in the Glutamatergic Synapse could lead to the identification of new pharmaceutical targets for the therapy of CNS disorders.

  • Postsynaptic density–membrane associated guanylate kinase proteins (PSD–MAGUKs) and their role in CNS disorders
    Neuroscience, 2008
    Co-Authors: Elena Marcello, Fabrizio Gardoni, M Di Luca
    Abstract:

    Membrane associated guanylate kinase proteins (MAGUKs) play a key role in the regulation of the intracellular trafficking and synaptic localization of ionotropic glutamate receptors. In particular, the postsynaptic density-95-like subfamily of MAGUKs (PSD-MAGUKs) organizes ionotropic glutamate receptors and their associated signaling proteins in the postsynaptic density of the excitatory Synapse regulating the strength of synaptic activity. Several recent observations clearly put forward the idea that alterations of PSD-MAGUK protein function such as alterations of PSD-MAGUK protein interaction with N-methyl-D-aspartate (NMDA) receptors regulatory subunits are common events in several CNS disorders. With this view, a better knowledge and understanding of PSD-MAGUK function as well as of the molecular events regulating PSD-MAGUK-mediated interactions in the Glutamatergic Synapse could lead to the identification of new pharmaceutical targets for the therapy of CNS disorders.

  • MAGUK proteins: New targets for pharmacological intervention in the Glutamatergic Synapse
    European Journal of Pharmacology, 2008
    Co-Authors: Fabrizio Gardoni
    Abstract:

    In the postsynaptic density of excitatory Glutamatergic Synapses, membrane associated guanylate kinase (MAGUK) proteins, such as Post-Synaptic Density 95 (PSD-95), organize ionotropic glutamate receptors and their associated signalling proteins regulating the strength of synaptic activity. Modifications of MAGUK proteins function in the Glutamatergic Synapse such as alterations of MAGUK proteins interaction with N-Methyl-D-Aspartate (NMDA) receptors regulatory subunits are common events in several neurodegenerative disorders. Thus, a better knowledge and understanding of MAGUK structure and function as well as of the molecular events regulating MAGUK-mediated interactions in the Glutamatergic Synapse could lead to the identification of new targets for pharmaceutical intervention for neurodegenerative diseases.

  • new targets for pharmacological intervention in the Glutamatergic Synapse
    European Journal of Pharmacology, 2006
    Co-Authors: Fabrizio Gardoni, Monica Di Luca
    Abstract:

    Excitotoxicity is thought to be a major mechanism in many human disease states such as ischemia, trauma, epilepsy and chronic neurodegenerative disorders. Briefly, synaptic overactivity leads to the excessive release of glutamate that activates postsynaptic cell membrane receptors, which upon activation open their associated ion channel pore to produce ion influx. To date, although molecular basis of glutamate toxicity remain uncertain, there is general agreement that N-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors plays a key role in mediating at least some aspects of glutamate neurotoxicity. On this view, research has focused in the discovery of new compounds able to either reduce glutamate release or activation of postsynaptic NMDA receptors. Although NMDA receptor antagonists prevent excitotoxicity in cellular and animal models, these drugs have limited usefulness clinically. Side effects such as psychosis, nausea, vomiting, memory impairment, and neuronal cell death accompany complete NMDA receptor blockade, dramatizing the crucial role of the NMDA receptor in normal neuronal processes. Recently, however, well-tolerated compounds such as memantine has been shown to be able to block excitotoxic cell death in a clinically tolerated manner. Understanding the biochemical properties of the multitude of NMDA receptor subtypes offers the possibility of developing more effective and clinically useful drugs. The increasing knowledge of the structure and function of this postsynaptic NMDA complex may improve the identification of specific molecular targets whose pharmacological or genetic manipulation might lead to innovative therapies for brain disorders.

  • Pathophysiological implications of the structural organization of the excitatory Synapse.
    European journal of pharmacology, 1999
    Co-Authors: F Cattabeni, Fabrizio Gardoni, M Di Luca
    Abstract:

    The Glutamatergic Synapse is the key structure in the development of activity-dependent synaptic plasticity in the central nervous system. The analysis of the complex biochemical mechanisms at the basis of the long-term changes in synaptic efficacy have received a tremendous impulse by the observation that the post-synaptic constituents of the Synapse can be separated and purified through a simple procedure involving detergent treatment of synaptosomes and differential centrifugation. In this fraction, called post-synaptic density (PSD), the functional interactions of its constituents are preserved. The various subunits of ionotropic glutamate receptors are held in register with the presynaptic active zone through their interaction with linker proteins. N-methyl-D-aspartate (NMDA) subunits NR2A and NR2B, bind to the PSD protein called PSD-95, which in turn binds neuroligins, providing a handle for interacting with neurexin, located in the plasma membrane at the presynaptic active zone. Additional clustering of NMDA receptors is provided through the binding of NRI subunits to the cytoskeletal protein alpha-actinin-2. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate receptors are other important constituents of PSDs and bind to different anchoring proteins. Phosphorylation processes have long been known to modulate NMDA receptor functional activity: the finding that several protein kinases, particularly Ca2+/Calmodulin-dependent protein kinase II and protein tyrosine kinases of the src family, are major constituents of PSDs has allowed to demonstrate that these enzymes are localized in a strategic position of the Glutamatergic Synapse, so that their activation provides a means for NMDA receptor function regulation upon its activation. The relevance of these mechanisms has been demonstrated in experimental models of pathologies involving deficits in synaptic plasticity, such as in streptozotocin-induced diabetes and in an animal model of prenatal induced ablation of hippocampal neurons. Both animal models display disturbances in long-term potentiation and cognitive deficits, thus providing in vivo models to study pathology related changes in both the structure and the function of the excitatory Synapse.

Bruce Walmsley - One of the best experts on this subject based on the ideXlab platform.

David A Lynch - One of the best experts on this subject based on the ideXlab platform.

  • D-Serine and Serine Racemase Are Associated with PSD-95 and Glutamatergic Synapse Stability
    Frontiers in Cellular Neuroscience, 2016
    Co-Authors: Ariel A. Jacobi, Stewart A. Anderson, David A Lynch
    Abstract:

    D-serine is an endogenous coagonist at the glycine site of synaptic NMDA receptors (NMDARs), synthesized by serine racemase (SR) through conversion of L-serine. It is crucial for synaptic plasticity and is implicated in schizophrenia. Our previous studies demonstrated specific loss of SR, D-serine-responsive synaptic NMDARs, and Glutamatergic Synapses in cortical neurons lacking alpha7 nicotinic acetylcholine receptors, which promotes Glutamatergic Synapse formation and maturation during development. We thus hypothesize that D-serine and SR (D-serine/SR) are associated with Glutamatergic synaptic development. Using morphological and molecular studies in cortical neuronal cultures, we demonstrate that D-serine/SR are associated with PSD-95 and NMDARs in postsynaptic neurons and with Glutamatergic Synapse stability during synaptic development. Endogenous D-serine and SR colocalize with PSD-95, but not presynaptic vesicular glutamate transporter 1 (VGLUT1), in Glutamatergic Synapses of cultured cortical neurons. Low-density astrocytes in cortical neuronal cultures lack SR expression but contain enriched D-serine in large vesicle-like structures, suggesting possible synthesis of D-serine in postsynaptic neurons and storage in astrocytes. More interestingly, endogenous D-serine and SR colocalize with PSD-95 in the postsynaptic terminals of Glutamatergic Synapses during early and late synaptic development, implicating involvement of D-serine/SR in Glutamatergic synaptic development. Exogenous application of D-serine enhances the interactions of SR with PSD-95 and NR1, and increases the number of VGLUT1- and PSD-95-positive Glutamatergic Synapses, suggesting that exogenous D-serine enhances postsynaptic SR/PSD-95 signaling and stabilizes Glutamatergic Synapses during cortical synaptic development. This is blocked by NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP5) and 7-chlorokynurenic acid (7-CK), a specific antagonist at the glycine site of NMDARs, demonstrating that D-serine effects are mediated through postsynaptic NMDARs. Conversely, exogenous application of glycine has no such effects, suggesting D-serine, rather than glycine, modulates postsynaptic events. Taken together, our findings demonstrate that D-serine/SR are associated with PSD-95 and NMDARs in postsynaptic neurons and with Glutamatergic Synapse stability during synaptic development, implicating D-serine/SR as regulators of cortical synaptic and circuit development.

  • calpain and the Glutamatergic Synapse
    Frontiers in Bioscience, 2009
    Co-Authors: Shachee Doshi, David A Lynch
    Abstract:

    Calpain is a ubiquitous protease found in different tissue types and in many organisms including mammals. It generally does not destroy its large variety of substrates, but more commonly disrupts their function. In neurons, many of its substrates become dysregulated as a result of cleavage of their regulatory domain by this protease, leading to altered signaling between cells. In Glutamatergic synaptic transmission, direct targets of calpain include all of the major glutamate receptors: NMDA receptors, AMPA receptors and mGluR. By cleaving these receptors and associated intracellular proteins, calpain may regulate the physiology at Glutamatergic Synapses. As a result, calpain-mediated cleavage in neurons might not only be involved in pathological events like excitotoxicity, but may also have neuroprotective effects and roles in physiological synaptic transmission.