1,721,059 research outputs found
Role of anti-NMDA antibodies and complement in the modulation of hippocampal glutamatergic neurotransmission: relevance to autoimmune diseases
No full textProlonged activation of CXCR4 hampers the release-regulating activity of presynaptic NMDA receptors in rat hippocampal synaptosomes
No full textWe investigated the impact of the prolonged exposure of rat hippocampal synaptosomes to CXCL12 (3 nM) on the NMDA-mediated release of [ 3 H]D-aspartate ([ 3 H]D-Asp) or [ 3 H]noradrenaline ([ 3 H]NA). Synaptosomes were stimulated twice with NMDA/CXCL12 and the amount of the NMDA-evoked tritium release (S1 and S2) quantified to calculate the S2/S1 ratio. The S2/S1 ratio for both transmitters was drastically decreased by 3 nM CXCL12 between the two stimuli (CXCL12-treated synaptosomes) in a AMD3100-sensitive manner. The phosphorylation of the GluN1 subunit in Ser 896 was reduced in CXCL12-treated synaptosomes, while the overall amount of GluN1 and GluN2B proteins as well as the GluN2B insertion in synaptosomal plasmamembranes were unchanged. We conclude that the CXCR4/NMDA cross-talk is dynamically regulated by the time of activation of the CXCR4s. Our results unveil a functional cross-talk that might account for the severe impairments of central transmission that develop in pathological conditions characterized by CXCL12 overproduction
Environmental Training And Synaptic Functions In Young And Old Brain: A Presynaptic Perspective
No full textBACKGROUND: Aging is an unavoidable, physiological process that reduces the complexity and the plasticity of the synaptic contacts in Central Nervous System (CNS), having profound implications for human well-being. The term "cognitive reserve" refers to central cellular adaptations that augment the resilience of human brain to damage and aging. The term "Cognitive training" indicates the cultural, social and physical stimulations proposed as add-on therapy for the cure of central neurological diseases. "Cognitive training" reinforces the "cognitive reserve" permitting to counteract brain impairments and rejuvenating synaptic complexity. The research has begun investigating the clinical impact of the "cognitive training" in aged people, but additional work is needed to definitively assess its effectiveness. In particular, there is a need to understand, from a preclinical point of view, whether "cognitive training" promotes compensatory effects or, alternatively, if it elicits genuine recovery of neuronal defects. Although the translation from rodent studies to the clinical situation could be difficult, the results from pre-clinical models are of high clinical relevance, since they should allow a better understanding of the effects of environmental interventions in aging-associated chronic derangements in mammals. CONCLUSION: Data in literature and the recent results obtained in our laboratory concerning the impact of environmental stimulation on the presynaptic release of noradrenaline, glutamate and gamma amino butyric acid (GABA) suggest that these neurotransmitters undergo different adaptations during aging and that they are differently tuned by "cognitive training". The impact of "cognitive training" on neurotransmitter exocytosis might account for the cellular events involved in reinforcement of "cognitive reserve" in young and old animals
Immuno-Pharmacological Characterization of Presynaptic GluN3A-Containing NMDA Autoreceptors: Relevance to Anti-NMDA Receptor Autoimmune Diseases
No full textMouse hippocampal glutamatergic nerve endings express presynaptic release-regulating NMDA autoreceptors (NMDARs). The presence of GluN1, GluN2A, GluN2B, and GluN3A subunits in hippocampal vesicular glutamate transporter type 1-positive synaptosomes was confirmed with confocal microscopy. GluN2C, GluN2D, and GluN3B immunopositivity was scarcely present. Incubation of synaptosomes with the anti-GluN1, the anti-GluN2A, the anti-GluN2B, or the anti-GluN3A antibody prevented the 30 μM NMDA/1 μM glycine-evoked [ 3 H]d-aspartate ([ 3 H]d-ASP) release. The NMDA/glycine-evoked [ 3 H]d-ASP release was reduced by increasing the external protons, consistent with the participation of GluN1 subunits lacking the N1 cassette to the receptor assembly. The result also excludes the involvement of GluN1/GluN3A dimers into the NMDA-evoked overflow. Complement (1:300) released [ 3 H]d-ASP in a dizocilpine-sensitive manner, suggesting the participation of a NMDAR-mediated component in the releasing activity. Accordingly, the complement-evoked glutamate overflow was reduced in anti-GluN-treated synaptosomes when compared to the control. We speculated that incubation with antibodies had favored the internalization of NMDA receptors. Indeed, a significant reduction of the GluN1 and GluN2B proteins in the plasma membranes of anti-GluN1 or anti-GluN2B antibody-treated synaptosomes emerged in biotinylation studies. Altogether, our findings confirm the existence of presynaptic GluN3A-containing release-regulating NMDARs in mouse hippocampal glutamatergic nerve endings. Furthermore, they unveil presynaptic alteration of the GluN subunit insertion in synaptosomal plasma membranes elicited by anti-GluN antibodies that might be relevant to the central alterations occurring in patients suffering from autoimmune anti-NMDA diseases
Non-canonical Roles of Complement in the CNS: From Synaptic Organizer to Presynaptic Modulator of Glutamate Transmission
No full textThe central nervous system (CNS) is not an immune-privileged compartment, but it is intimately intertwined with the immune system. Among the components shared by the two compartments is the complement, a main constituent of innate immunity, which is also produced centrally and controls the development and organization of synaptic connections. Complement is considered a doubled-faced system that, besides controlling the physiological development of the central network, also subserves synaptic engulfment pivotal to the progression of neurodegenerative diseases. Quite interestingly, besides these “canonical” roles, evidence in the last two decades highlighted other “non-canonical” role(s), thereby complementing modulates chemical transmission at central synapsis. It emerged that glutamate is the preferential target of these “non-canonical” complement-induced effects, which include i) the control of the release of glutamate from neurons and astrocytes and ii) the control of the number and the functions of central glutamatergic receptor subtypes (i.e., the NMDA receptors, the AMPA/kainate receptors, and the metabotropic glutamate receptors) in plasma membranes. This review summarizes some of the available results supporting the role of complement as a “modulator” of central glutamate transmission, paying particular attention to those events that occur presynaptically. Taking into consideration the enormous progress in complement pharmacology and the increasing number of therapeutics in clinical trials, deepening our knowledge of these” non-canonical” role(s) could pave the road to new therapeutic approaches for the management of central neurological diseases
Progress in metamodulation and receptor-receptor interaction: From physiology to pathology and therapy
No full text: The organization and the role of receptor-receptor interaction (RRI) and metamodulation in physiological conditions have been extensively analyzed and discussed. In this Special Issue of Neuropharmacology, we review recent advances in the understanding of the RRI and the mechanisms underlying its adaptation that could be relevant to the etiopathogenesis of central neuropsychiatric disorders, as well as to the development of new therapeutic approaches to control the activity and to restore the physiological functions, posing the basis for new targeted pharmacological interventions.The organization and the role of receptor-receptor interaction (RRI) and metamodulation in physiological conditions have been extensively analyzed and discussed. In this Special Issue of Neuropharmacology, we review recent advances in the understanding of the RRI and the mechanisms underlying its adaptation that could be relevant to the etiopathogenesis of central neuropsychiatric disorders, as well as to the development of new therapeutic approaches to control the activity and to restore the physiological functions, posing the basis for new targeted pharmacological interventions
Anti-NMDA and Anti-AMPA Receptor Antibodies in Central Disorders: Preclinical Approaches to Assess Their Pathological Role and Translatability to Clinic
No full textAutoantibodies against NMDA and AMPA receptors have been identified in the central nervous system of patients suffering from brain disorders characterized by neurological and psychiatric symptoms. It has been demonstrated that these autoantibodies can affect the functions and/or the expression of the targeted receptors, altering synaptic communication. The importance to clarify, in preclinical models, the molecular mechanisms involved in the autoantibody-mediated effects has emerged in order to understand their pathogenic role in central disorders, but also to propose new therapeutic approaches for preventing the deleterious central consequences. In this review, we describe some of the available preclinical literature concerning the impact of antibodies recognizing NMDA and AMPA receptors in neurons. This review discusses the cellular events that would support the detrimental roles of the autoantibodies, also illustrating some contrasting findings that in our opinion deserve attention and further investigations before translating the preclinical observations to clinic
The Anti-Aggregative Peptide KLVFF Mimics Aβ1-40 in the Modulation of Nicotinic Receptors: Implications for Peptide-Based Therapy
No full textIn recent years, the inhibition of beta-amyloid (Aβ) aggregation has emerged as a potential strategy for Alzheimer’s disease. KLVFF, a small peptide corresponding to the aminoacidic sequence 16-20 of Aβ, reduces Aβ fibrillation dose dependently. Therefore, the toxic and functional characterization of its brain activity is fundamental for clarifying its potential therapeutic role. Accordingly, we studied the modulatory role of KLVFF on the cholinergic receptors regulating dopamine and noradrenaline release in rat synaptosomes. Nicotinic receptors on dopaminergic nerve terminals in the nucleus acccumbens are inhibited by KLVFF, which closely resembles full-length Aβ1-40. Moreover, KLVFF entrapped in synaptosomes does not modify the nicotinic receptor’s function, suggesting that external binding to the receptor is required for its activity. The cholinergic agent desformylflustrabromine counteracts the KLVFF effect. Remarkably, muscarinic receptors on dopaminergic terminals and nicotinic receptors regulating noradrenaline release in the hippocampus are completely insensitive to KLVFF. Based on our findings, KLVFF mimics Aβ1-40 as a negative modulator of specific nicotinic receptor subtypes affecting dopamine transmission in the rat brain. Therefore, new pharmacological strategies using the anti-aggregative properties of KLVFF need to be evaluated for potential interference with nicotinic receptor-mediated transmission
Metamodulation of presynaptic NMDA receptors: New perspectives for pharmacological interventions
No full text: Metamodulation shifted the scenario of the central neuromodulation from a simplified unimodal model to a multimodal one. It involves different receptors/membrane proteins physically associated or merely colocalized that act in concert to control the neuronal functions influencing each other. Defects or maladaptation of metamodulation would subserve neuropsychiatric disorders or even synaptic adaptations relevant to drug dependence. Therefore, this "vulnerability" represents a main issue to be deeply analyzed to predict its aetiopathogenesis, but also to propose targeted pharmaceutical interventions. The review focusses on presynaptic release-regulating NMDA receptors and on some of the mechanisms of their metamodulation described in the literature. Attention is paid to the interactors, including both ionotropic and metabotropic receptors, transporters and intracellular proteins, which metamodulate their responsiveness in physiological conditions but also undergo adaptation that are relevant to neurological dysfunctions. All these structures are attracting more and more the interest as promising druggable targets for the treatment of NMDAR-related central diseases: these substances would not exert on-off control of the colocalized NMDA receptors (as usually observed with NMDAR full agonists/antagonists), but rather modulate their functions, with the promise of limiting side effects that would favor their translation from preclinic to clinic
- …
