Voltage-independent GluN2A-type NMDA receptor Ca 2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in mice.

Autor: Bertocchi I; Departments Molecular Neurobiology and Physiology at the Max Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany.; Research Group of the Max Planck Institute for Medical Research at the Institute for Anatomy and Cell Biology of the Heidelberg University, Im Neuenheimer Feld 307, 69120, Heidelberg, Germany.; Department of Neuroscience Rita Levi Montalcini, University of Turin, Via Cherasco 15, 10126, Torino, Italy.; Neuroscience Institute-Cavalieri-Ottolenghi Foundation (NICO), Laboratory of Neuropsychopharmacology, Regionale Gonzole 10, 10043 Orbassano, Torino, Italy., Eltokhi A; Research Group of the Max Planck Institute for Medical Research at the Institute for Anatomy and Cell Biology of the Heidelberg University, Im Neuenheimer Feld 307, 69120, Heidelberg, Germany.; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Otfried-Müller Str. 27, 72076, Tübingen, Germany., Rozov A; Departments Molecular Neurobiology and Physiology at the Max Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany.; Department of Physiology and Pathophysiology, Heidelberg University, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.; OpenLab of Neurobiology, Kazan Federal University, 8 Kremlyovskaya Street, Kazan, 420008, Russian Federation.; Federal Center of Brain Research and Neurotechnologies, Ostrovityanova Str 1/10, Moscow, 117997, Russia., Chi VN; Department of Physiology and Pathophysiology, Heidelberg University, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany., Jensen V; Department of Molecular Medicine, Division of Physiology, Institute of Basic Medical Sciences, University of Oslo, Sognsvannsveien 9, 0372, Oslo, Norway., Bus T; Departments Molecular Neurobiology and Physiology at the Max Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany.; Research Group of the Max Planck Institute for Medical Research at the Institute for Anatomy and Cell Biology of the Heidelberg University, Im Neuenheimer Feld 307, 69120, Heidelberg, Germany., Pawlak V; Departments Molecular Neurobiology and Physiology at the Max Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany.; Department of Behavior and Brain Organization, Research Center Caesar, Ludwig-Erhard-Allee 2, 53175, Bonn, Germany., Serafino M; Departments Molecular Neurobiology and Physiology at the Max Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany.; FARMA-DERMA s.r.l. Via dell'Artigiano 6-8, 40010, Sala Bolognese, Italy., Sonntag H; Departments Molecular Neurobiology and Physiology at the Max Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany.; Research Group of the Max Planck Institute for Medical Research at the Institute for Anatomy and Cell Biology of the Heidelberg University, Im Neuenheimer Feld 307, 69120, Heidelberg, Germany., Yang B; Departments Molecular Neurobiology and Physiology at the Max Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany.; Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 JieFang Road, Wuhan, Hubei, 430030, China., Burnashev N; Departments Molecular Neurobiology and Physiology at the Max Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany.; INSERM UMR 1249 Mediterranean Institute of Neurobiology (INMED), Aix-Marseille University, Parc Scientifique de Luminy, 163 avenue de Luminy BP13, 13273, Marseille Cedex 09, France., Li SB; Departments Molecular Neurobiology and Physiology at the Max Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany.; Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 1201 Welch Road, Stanford, CA, 94305, USA.; Wu Tsai Neurosciences Institute, Stanford University, Stanford Way, Rm E152, Stanford, CA, 94305, USA., Obenhaus HA; Departments Molecular Neurobiology and Physiology at the Max Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany.; Research Group of the Max Planck Institute for Medical Research at the Institute for Anatomy and Cell Biology of the Heidelberg University, Im Neuenheimer Feld 307, 69120, Heidelberg, Germany.; Kavli Institute for Systems Neuroscience, Faculty of Medicine and Health Sciences, NTNU, Postboks 8905, NO-7491, Trondheim, Norway., Both M; Department of Physiology and Pathophysiology, Heidelberg University, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany., Niewoehner B; Department of Experimental Psychology, University of Oxford, Radcliffe Observatory, Anna Watts Building, Woodstock Rd, Oxford, OX2 6GG, UK., Single FN; Departments Molecular Neurobiology and Physiology at the Max Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany.; Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Friedrich-Ebert-Str. 68, 51429, Bergisch Gladbach, Germany., Briese M; Department of Experimental Psychology, University of Oxford, Radcliffe Observatory, Anna Watts Building, Woodstock Rd, Oxford, OX2 6GG, UK.; Institute of Clinical Neurobiology, University Hospital Wuerzburg, Versbacherstraße 5, 97080, Wuerzburg, Germany., Boerner T; Department of Experimental Psychology, University of Oxford, Radcliffe Observatory, Anna Watts Building, Woodstock Rd, Oxford, OX2 6GG, UK., Gass P; RG Animal Models in Psychiatry, Animal Models Psychatry, Central Institute of Mental Health (CIMH), Faculty Mannheim, Heidelberg University, J5, 68159, Mannheim, Germany., Rawlins JNP; Department of Experimental Psychology, University of Oxford, Radcliffe Observatory, Anna Watts Building, Woodstock Rd, Oxford, OX2 6GG, UK., Köhr G; Departments Molecular Neurobiology and Physiology at the Max Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany.; Department of Neurophysiology, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany., Bannerman DM; Department of Experimental Psychology, University of Oxford, Radcliffe Observatory, Anna Watts Building, Woodstock Rd, Oxford, OX2 6GG, UK. Rolf.Sprengel@mpimf-heidelberg.mpg.de., Sprengel R; Departments Molecular Neurobiology and Physiology at the Max Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany. David.Bannerman@psy.ox.ac.uk.; Research Group of the Max Planck Institute for Medical Research at the Institute for Anatomy and Cell Biology of the Heidelberg University, Im Neuenheimer Feld 307, 69120, Heidelberg, Germany. David.Bannerman@psy.ox.ac.uk.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2021 Jan 08; Vol. 4 (1), pp. 59. Date of Electronic Publication: 2021 Jan 08.
DOI: 10.1038/s42003-020-01538-4
Abstrakt: The NMDA receptor-mediated Ca 2+  signaling during simultaneous pre- and postsynaptic activity is critically involved in synaptic plasticity and thus has a key role in the nervous system. In GRIN2-variant patients alterations of this coincidence detection provoked complex clinical phenotypes, ranging from reduced muscle strength to epileptic seizures and intellectual disability. By using our gene-targeted mouse line (Grin2a N615S ), we show that voltage-independent glutamate-gated signaling of GluN2A-containing NMDA receptors is associated with NMDAR-dependent audiogenic seizures due to hyperexcitable midbrain circuits. In contrast, the NMDAR antagonist MK-801-induced c-Fos expression is reduced in the hippocampus. Likewise, the synchronization of theta- and gamma oscillatory activity is lowered during exploration, demonstrating reduced hippocampal activity. This is associated with exploratory hyperactivity and aberrantly increased and dysregulated levels of attention that can interfere with associative learning, in particular when relevant cues and reward outcomes are disconnected in space and time. Together, our findings provide (i) experimental evidence that the inherent voltage-dependent Ca 2+ signaling of NMDA receptors is essential for maintaining appropriate responses to sensory stimuli and (ii) a mechanistic explanation for the neurological manifestations seen in the NMDAR-related human disorders with GRIN2 variant-meidiated intellectual disability and focal epilepsy.
Databáze: MEDLINE
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