{"doi":"10.3389/fncel.2022.916626","title":"Synaptic NMDA receptor activity at resting membrane potentials","abstract":"<jats:p>NMDA receptors (NMDARs) are crucial for glutamatergic synaptic signaling in the mammalian central nervous system. When activated by glutamate and glycine/D-serine, the NMDAR ion channel can open, but current flux is further regulated by voltage-dependent block conferred by extracellular Mg<jats:sup>2+</jats:sup> ions. The unique biophysical property of ligand- and voltage-dependence positions NMDARs as synaptic coincidence detectors, controlling a major source of synaptic Ca<jats:sup>2+</jats:sup> influx. We measured synaptic currents in layer 2/3 neurons after stimulation in layer 4 of somatosensory cortex and found measurable NMDAR currents at all voltages tested. This NMDAR current did not require concurrent AMPAR depolarization. In physiological ionic conditions, the NMDAR current response at negative potentials was enhanced relative to ionic conditions typically used in slice experiments. NMDAR activity was also seen in synaptic recordings from hippocampal CA1 neurons, indicating a general property of NMDAR signaling. Using a fluorescent Ca<jats:sup>2+</jats:sup> indicator, we measured responses to stimulation in layer 4 at individual synaptic sites, and Ca<jats:sup>2+</jats:sup> influx could be detected even with AMPARs blocked. In current clamp recordings, we found that resting membrane potential was hyperpolarized by ∼7 mV and AP firing threshold depolarized by ∼4 mV in traditional compared to physiological ionic concentrations, and that NMDARs contribute to EPSPs at resting membrane potentials. These measurements demonstrate that, even in the presence of extracellular Mg<jats:sup>2+</jats:sup> and absence of postsynaptic depolarization, NMDARs contribute to synaptic currents and Ca<jats:sup>2+</jats:sup> influx.</jats:p>","journal":"Frontiers in Cellular Neuroscience","year":2022,"id":641381,"datarank":0.4636563680037475,"base_score":3.091042453358316,"endowment":3.091042453358316,"self_citation_contribution":0.4636563680037475,"citation_network_contribution":0.0,"self_endowment_contribution":0.4636563680037475,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1667604,"name":"Brett C. 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This NMDAR current did not require concurrent AMPAR depolarization. In physiological ionic conditions, the NMDAR current response at negative potentials was enhanced relative to ionic conditions typically used in slice experiments. NMDAR activity was also seen in synaptic recordings from hippocampal CA1 neurons, indicating a general property of NMDAR signaling. Using a fluorescent Ca 2+ indicator, we measured responses to stimulation in layer 4 at individual synaptic sites, and Ca 2+ influx could be detected even with AMPARs blocked. In current clamp recordings, we found that resting membrane potential was hyperpolarized by ∼7 mV and AP firing threshold depolarized by ∼4 mV in traditional compared to physiological ionic concentrations, and that NMDARs contribute to EPSPs at resting membrane potentials. These measurements demonstrate that, even in the presence of extracellular Mg 2+ and absence of postsynaptic depolarization, NMDARs contribute to synaptic currents and Ca 2+ influx.","is_dataset_classified":null,"base_score":3.091042453358316,"endowment":3.091042453358316,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35928574","pmcid":"PMC9345169","openalex_id":"https://openalex.org/W4286219986","authors":[],"funders":[{"funder_name":"European Research Council","grant_id":"802354","title":"Novel NMDA receptor signaling in cortical synaptic depression"}],"total_grants":1,"fwci":1.6558,"citation_percentile":0.83026017,"influential_citations":0,"citation_trend":[{"year":2023,"count":4},{"year":2024,"count":7},{"year":2025,"count":7},{"year":2026,"count":2}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.frontiersin.org/articles/10.3389/fncel.2022.916626/pdf","host_type":"journal"},{"url":"https://www.frontiersin.org/articles/10.3389/fncel.2022.916626/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3389/fncel.2022.916626","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/35928574","host_type":"repository"},{"url":"https://doaj.org/article/7adbdb2737424e8aaf11bce3b5539c99","host_type":"repository"},{"url":"https://resolver.sub.uni-goettingen.de/purl?gro-2/113889","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9345169","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC9345169","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC9345169?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.3389/fncel.2022.916626","host_type":""}],"fields_of_study":["Neuroscience and Neuropharmacology Research","Photoreceptor and optogenetics research","Ion channel regulation and function","0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":[],"keywords":["NMDA receptor","Neuroscience","Chemistry","Receptor","Biology","Biochemistry","Hippocampus","Glutamate","NMDA receptors","Somatosensory cortex","Postsynaptic Signaling","Neurosciences. 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