N-methyl-D-aspartate receptors and depression
linking psychopharmacology, pathology and physiology in a unifying hypothesis for the epigenetic code of neural plasticity
Informazioni aggiuntive
Autori
Comani S.,
De Martin S.,
Mattarei A.,
Guidetti C.,
Pappagallo M.,
Folli F.,
Alimonti A.,
Manfredi P. L.
Tipo
Articolo pubblicato in rivista scientifica
Anno
2023
Lingua
Inglese
Sommario
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 Ca2+ 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 Ca2+ influx. Quanta of Ca2+ via NMDARs activate enzymatic pathways, epigenetically regulating synaptic protein homeostasis and synaptic receptor expression; thereby, Ca2+ quanta via NMDARs control the balance between long-term potentiation and long-term depression. This NMDAR Ca2+ quantal hypothesis for the epigenetic code of neural plasticity integrates recent psychopharmacology findings into established physiological and pathological mechanisms of brain function.
Parole chiave
AMPA, Ca2+, Endorphins, Glutamate, Mg2+, Major depressive disorder, Neural plasticity, NMDA
Periodico
Pharmaceuticals
Volume
17
Numero ( Mese )
12
Pagine (o numero dell’articolo)
1618
Diffusione
Licenza
CC BY
Visibilità
Pubblico
Status open access
Gold
