GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer’s Disease Models
| Autor: | Hilda Solanoy, Morgan Sheng, Gui-Qiu Yu, Jesse E. Hanson, Gauri Deshmukh, Benjamin D. Sellers, Tzu-Ming Wang, Yelin Chen, Justin Elstrott, Connie Chan, Zhiyu Jiang, Thomas A. Kim, David H. Hackos, Jacob Schwarz, Jorge J. Palop, T. Michael Gill, Matthew Volgraf, Keran Ma, Jeffrey Simms, Kimberly Scearce-Levie, Martin Weber, Bianca M. Liederer, Sandrine Saillet, Abdullah S. Khan, Robby M. Weimer, Benjamin Liu |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cyclopropanes Male Aging Medical Physiology Epilepsies Myoclonic Electroencephalography Epilepsies Neurodegenerative Inbred C57BL Alzheimer's Disease memory Epilepsy Mice 0302 clinical medicine Cognition Receptors 2.1 Biological and endogenous factors EEG SCN1A Aetiology lcsh:QH301-705.5 MK-801 learning Behavior Animal medicine.diagnostic_test musculoskeletal neural and ocular physiology Brain medicine.anatomical_structure Neurological NMDA receptor Mental health N-Methyl-D-Aspartate Allosteric modulator Interneuron Intellectual and Developmental Disabilities (IDD) Allosteric regulation CHO Cells interneuron Receptors N-Methyl-D-Aspartate Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Cricetulus Dravet syndrome Allosteric Regulation Alzheimer Disease Nitriles Behavioral and Social Science medicine Acquired Cognitive Impairment Animals Humans Behavior business.industry Animal Nav1.1 Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) medicine.disease Brain Disorders Mice Inbred C57BL Disease Models Animal Thiazoles 030104 developmental biology nervous system lcsh:Biology (General) Disease Models Pyrazoles epilepsy Dementia Biochemistry and Cell Biology J20 business Myoclonic APP Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 30, Iss 2, Pp 381-396.e4 (2020) Elsevier Cell reports, vol 30, iss 2 Cell reports |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY NMDA receptors (NMDARs) play subunit-specific roles in synaptic function and are implicated in neuropsychiatric and neurodegenerative disorders. However, the in vivo consequences and therapeutic potential of pharmacologically enhancing NMDAR function via allosteric modulation are largely un-known. We examine the in vivo effects of GNE-0723, a positive allosteric modulator of GluN2A-subunit-containing NMDARs, on brain network and cognitive functions in mouse models of Dravet syndrome (DS) and Alzheimer’s disease (AD). GNE-0723 use dependently potentiates synaptic NMDA receptor currents and reduces brain oscillation power with a predominant effect on low-frequency (12–20 Hz) oscillations. Interestingly, DS and AD mouse models display aberrant low-frequency oscillatory power that is tightly correlated with network hypersynchrony. GNE-0723 treatment reduces aberrant low-frequency oscillations and epileptiform discharges and improves cognitive functions in DS and AD mouse models. GluN2A-subunit-containing NMDAR enhancers may have therapeutic benefits in brain disorders with network hypersynchrony and cognitive impairments. Graphical Abstract In Brief Hanson et al. examine the therapeutic effects of enhancing GluN2A-subunit-containing NMDAR function in Dravet syndrome and Alzheimer’s disease mice. GNE-0723 treatment reduces aberrant low-frequency oscillations and epileptiform discharges and improves cognitive functions in both disease models. GluN2A NMDAR enhancers may benefit brain disorders with network hypersynchrony and cognitive impairments. |
| Databáze: | OpenAIRE |
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