title: Regulation of extrasynaptic signaling by polysialylated NCAM: Impact for synaptic plasticity and cognitive functions.
abstract: The activation of synaptic N-methyl-d-aspartate-receptors (NMDARs) is crucial for induction of synaptic plasticity and supports cell survival, whereas activation of extrasynaptic NMDARs inhibits long-term potentiation and triggers neurodegeneration. A soluble polysialylated form of the neural cell adhesion molecule (polySia-NCAM) suppresses signaling through peri-/extrasynaptic GluN2B-containing NMDARs. Genetic or enzymatic manipulations blocking this mechanism result in impaired synaptic plasticity and learning, which could be repaired by reintroduction of polySia, or inhibition of either GluN1/GluN2B receptors or downstream signaling through RasGRF1 and p38 MAP kinase. Ectodomain shedding of NCAM, and hence generation of soluble NCAM, is controlled by metalloproteases of a disintegrin and metalloprotease (ADAM) family. As polySia-NCAM is predominantly associated with GABAergic interneurons in the prefrontal cortex, it is noteworthy that EphrinA5/EphA3-induced ADAM10 activity promotes polySia-NCAM shedding in these neurons. Thus, in addition to the well-known regulation of synaptic NMDARs by the secreted molecule Reelin, shed polySia-NCAM may restrain activation of extrasynaptic NMDARs. These data support a concept that GABAergic interneuron-derived extracellular proteins control the balance in synaptic/extrasynaptic NMDAR-mediated signaling in principal cells. Strikingly, dysregulation of Reelin or polySia expression is linked to schizophrenia. Thus, targeting of the GABAergic interneuron-principle cell communication and restoring the balance in synaptic/extrasynaptic NMDARs represent promising strategies for treatment of psychiatric diseases.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, 39120 Magdeburg, Germany.
authors.forename: Hristo
authors.initials: H
authors.lastname: Varbanov
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, 39120 Magdeburg, Germany; Medical Faculty, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany. Electronic address: alexander.dityatev@dzne.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dityatev
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000502:physiology; D003071:Cognition; D006801:Humans; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity; D011499:Protein Processing, Post-Translational; D000091042:Reelin Protein; D012794:Sialic Acids / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: D019006:Neural Cell Adhesion Molecules; D000091042:Reelin Protein; D012794:Sialic Acids; C021319:polysialic acid; C000717127:RELN protein, human
keywords: Hippocampus; LTP; Learning; NMDA receptor; PSA-NCAM; Polysialic acid; Schizophrenia; Synaptic plasticity; mPFC