N-methyl-D-aspartate Receptors and Depression: Linking Psychopharmacology, Pathology and Physiology in a Unifying Hypothesis for the Epigenetic Code of Neural Plasticity
Uncompetitive NMDAR (N-methyl-D-aspartate receptor) antagonists restore impaired neural plasticity, reverse depressive-like behavior in animal models, and relieve major depressive disorder (MDD) in humans. This review integrates recent findings from in silico, in vitro, in vivo, and human studies of...
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2024-11-01
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| author | Stefano Comai Sara De Martin Andrea Mattarei Clotilde Guidetti Marco Pappagallo Franco Folli Andrea Alimonti Paolo L. Manfredi |
| author_facet | Stefano Comai Sara De Martin Andrea Mattarei Clotilde Guidetti Marco Pappagallo Franco Folli Andrea Alimonti Paolo L. Manfredi |
| author_sort | Stefano Comai |
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| description | Uncompetitive NMDAR (N-methyl-D-aspartate receptor) antagonists restore impaired neural plasticity, reverse depressive-like behavior in animal models, and relieve major depressive disorder (MDD) in humans. This review integrates recent findings from in silico, in vitro, in vivo, and human studies of uncompetitive NMDAR antagonists into the extensive body of knowledge on NMDARs and neural plasticity. Uncompetitive NMDAR antagonists are activity-dependent channel blockers that preferentially target hyperactive GluN2D subtypes because these subtypes are most sensitive to activation by low concentrations of extracellular glutamate and are more likely activated by certain pathological agonists and allosteric modulators. Hyperactivity of GluN2D subtypes in specific neural circuits may underlie the pathophysiology of MDD. We hypothesize that neural plasticity is epigenetically regulated by precise Ca<sup>2+</sup> quanta entering cells via NMDARs. Stimuli reach receptor cells (specialized cells that detect specific types of stimuli and convert them into electrical signals) and change their membrane potential, regulating glutamate release in the synaptic cleft. Free glutamate binds ionotropic glutamatergic receptors regulating NMDAR-mediated Ca<sup>2+</sup> influx. Quanta of Ca<sup>2+</sup> via NMDARs activate enzymatic pathways, epigenetically regulating synaptic protein homeostasis and synaptic receptor expression; thereby, Ca<sup>2+</sup> quanta via NMDARs control the balance between long-term potentiation and long-term depression. This NMDAR Ca<sup>2+</sup> quantal hypothesis for the epigenetic code of neural plasticity integrates recent psychopharmacology findings into established physiological and pathological mechanisms of brain function. |
| format | Article |
| id | doaj-art-3a2d3cc81c1247ce90eb45c3f01e0fa6 |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj-art-3a2d3cc81c1247ce90eb45c3f01e0fa62024-12-27T14:45:52ZengMDPI AGPharmaceuticals1424-82472024-11-011712161810.3390/ph17121618N-methyl-D-aspartate Receptors and Depression: Linking Psychopharmacology, Pathology and Physiology in a Unifying Hypothesis for the Epigenetic Code of Neural PlasticityStefano Comai0Sara De Martin1Andrea Mattarei2Clotilde Guidetti3Marco Pappagallo4Franco Folli5Andrea Alimonti6Paolo L. Manfredi7Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35121 Padua, ItalyDepartment of Pharmaceutical and Pharmacological Sciences, University of Padua, 35121 Padua, ItalyDepartment of Pharmaceutical and Pharmacological Sciences, University of Padua, 35121 Padua, ItalyChild Neuropsychiatry Unit, Department of Neuroscience, IRCCS Bambino Gesù Pediatric Hospital, 00165 Rome, ItalyRelmada Therapeutics, Inc., Coral Gables, FL 33134, USADepartment of Health Sciences, University of Milan, 20141 Milan, ItalyThe Institute of Oncology Research, Università della Svizzera Italiana, 6500 Bellinzona, SwitzerlandRelmada Therapeutics, Inc., Coral Gables, FL 33134, USAUncompetitive NMDAR (N-methyl-D-aspartate receptor) antagonists restore impaired neural plasticity, reverse depressive-like behavior in animal models, and relieve major depressive disorder (MDD) in humans. This review integrates recent findings from in silico, in vitro, in vivo, and human studies of uncompetitive NMDAR antagonists into the extensive body of knowledge on NMDARs and neural plasticity. Uncompetitive NMDAR antagonists are activity-dependent channel blockers that preferentially target hyperactive GluN2D subtypes because these subtypes are most sensitive to activation by low concentrations of extracellular glutamate and are more likely activated by certain pathological agonists and allosteric modulators. Hyperactivity of GluN2D subtypes in specific neural circuits may underlie the pathophysiology of MDD. We hypothesize that neural plasticity is epigenetically regulated by precise Ca<sup>2+</sup> quanta entering cells via NMDARs. Stimuli reach receptor cells (specialized cells that detect specific types of stimuli and convert them into electrical signals) and change their membrane potential, regulating glutamate release in the synaptic cleft. Free glutamate binds ionotropic glutamatergic receptors regulating NMDAR-mediated Ca<sup>2+</sup> influx. Quanta of Ca<sup>2+</sup> via NMDARs activate enzymatic pathways, epigenetically regulating synaptic protein homeostasis and synaptic receptor expression; thereby, Ca<sup>2+</sup> quanta via NMDARs control the balance between long-term potentiation and long-term depression. This NMDAR Ca<sup>2+</sup> quantal hypothesis for the epigenetic code of neural plasticity integrates recent psychopharmacology findings into established physiological and pathological mechanisms of brain function.https://www.mdpi.com/1424-8247/17/12/1618AMPACa<sup>2+</sup>endorphinsglutamateMg<sup>2+</sup>major depressive disorder |
| spellingShingle | Stefano Comai Sara De Martin Andrea Mattarei Clotilde Guidetti Marco Pappagallo Franco Folli Andrea Alimonti Paolo L. Manfredi N-methyl-D-aspartate Receptors and Depression: Linking Psychopharmacology, Pathology and Physiology in a Unifying Hypothesis for the Epigenetic Code of Neural Plasticity Pharmaceuticals AMPA Ca<sup>2+</sup> endorphins glutamate Mg<sup>2+</sup> major depressive disorder |
| title | N-methyl-D-aspartate Receptors and Depression: Linking Psychopharmacology, Pathology and Physiology in a Unifying Hypothesis for the Epigenetic Code of Neural Plasticity |
| title_full | N-methyl-D-aspartate Receptors and Depression: Linking Psychopharmacology, Pathology and Physiology in a Unifying Hypothesis for the Epigenetic Code of Neural Plasticity |
| title_fullStr | N-methyl-D-aspartate Receptors and Depression: Linking Psychopharmacology, Pathology and Physiology in a Unifying Hypothesis for the Epigenetic Code of Neural Plasticity |
| title_full_unstemmed | N-methyl-D-aspartate Receptors and Depression: Linking Psychopharmacology, Pathology and Physiology in a Unifying Hypothesis for the Epigenetic Code of Neural Plasticity |
| title_short | N-methyl-D-aspartate Receptors and Depression: Linking Psychopharmacology, Pathology and Physiology in a Unifying Hypothesis for the Epigenetic Code of Neural Plasticity |
| title_sort | n methyl d aspartate receptors and depression linking psychopharmacology pathology and physiology in a unifying hypothesis for the epigenetic code of neural plasticity |
| topic | AMPA Ca<sup>2+</sup> endorphins glutamate Mg<sup>2+</sup> major depressive disorder |
| url | https://www.mdpi.com/1424-8247/17/12/1618 |
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