Postsynaptic serine racemase regulates NMDA receptor function
Postsynaptic serine racemase regulates NMDA receptor function
Abstract D-serine is the primary NMDA receptor (NMDAR) co-agonist at mature forebrain synapses and is synthesized by the enzyme serine racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic D-serine remains limited. Though early studies suggested D-serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and D-serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons, as well as the presence of SR in human hippocampal synaptosomes. In addition, using a single-neuron genetic approach in SR conditional knockout mice, we demonstrate a cell-autonomous role for SR in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses. Importantly, single-neuron genetic deletion of SR resulted in the elimination of LTP at one month of age. Interestingly, there was a restoration of LTP by two months of age that was associated with an upregulation of synaptic GluN2B. Our findings support a cell-autonomous role for postsynaptic neuronal SR in regulating synaptic NMDAR function and suggests a possible autocrine mode of D-serine action.
Wong Jonathan M.、Berciu Cristina、Harvey Theresa L.、DeChellis-Marks Michael R.、Coyle Joseph T.、Balu Darrick T.、Gray John A.、MacDonald Matthew L.、Barragan Eden V.、Glausier Jill R.、Folorunso Oluwarotimi
Center for Neuroscience, University of California Davis||Neuroscience Graduate Group, University of California DavisDepartment of Psychiatry, Harvard Medical SchoolDepartment of Psychiatry, Harvard Medical SchoolDepartment of Psychiatry, University of Pittsburgh||Biomedical Mass Spectrometry Center, University of Pittsburgh||Center for Neuroscience, University of PittsburghDepartment of Psychiatry, Harvard Medical School||Laboratory for Psychiatric and Molecular Neuroscience, McLean HospitalDepartment of Psychiatry, Harvard Medical School||Translational Psychiatry Laboratory, McLean HospitalCenter for Neuroscience, University of California Davis||Department of Neurology, University of California DavisDepartment of Psychiatry, University of Pittsburgh||Biomedical Mass Spectrometry Center, University of PittsburghCenter for Neuroscience, University of California Davis||Neuroscience Graduate Group, University of California DavisDepartment of Psychiatry, University of PittsburghDepartment of Psychiatry, Harvard Medical School||Translational Psychiatry Laboratory, McLean Hospital
基础医学神经病学、精神病学生理学
Wong Jonathan M.,Berciu Cristina,Harvey Theresa L.,DeChellis-Marks Michael R.,Coyle Joseph T.,Balu Darrick T.,Gray John A.,MacDonald Matthew L.,Barragan Eden V.,Glausier Jill R.,Folorunso Oluwarotimi.Postsynaptic serine racemase regulates NMDA receptor function[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2020.06.16.155572.点此复制
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