D-serine and serine racemase are associated with PSD-95 and glutamatergic synapse stability
D-serine is an endogenous coagonist at the glycine site of synaptic NMDA receptors (NMDARs), synthesized by serine racemase (SR) through conversion of L-serine. It is crucial for synaptic plasticity and is implicated in schizophrenia. Our previous studies demonstrated specific loss of SR, D-serine-r...
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doaj-9d6a82d2efbc43409202a4249904b4d22020-11-24T23:22:54ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022016-02-011010.3389/fncel.2016.00034174146D-serine and serine racemase are associated with PSD-95 and glutamatergic synapse stabilityHong eLin0Ariel A. Jacobi1Ariel A. Jacobi2Stewart A. Anderson3Stewart A. Anderson4David R. Lynch5David R. Lynch6The Children's Hospital of PhiladelphiaThe Children's Hospital of PhiladelphiaUniversity of Pennsylvania School of Arts and SciencesThe Children's Hospital of PhiladelphiaUniversity of Pennsylvania Perelman School of MedicineThe Children's Hospital of PhiladelphiaUniversity of Pennsylvania Perelman School of MedicineD-serine is an endogenous coagonist at the glycine site of synaptic NMDA receptors (NMDARs), synthesized by serine racemase (SR) through conversion of L-serine. It is crucial for synaptic plasticity and is implicated in schizophrenia. Our previous studies demonstrated specific loss of SR, D-serine-responsive synaptic NMDARs, and glutamatergic synapses in cortical neurons lacking alpha7 nicotinic acetylcholine receptors, which promotes glutamatergic synapse formation and maturation during development. We thus hypothesize that D-serine and SR (D-serine/SR) are associated with glutamatergic synaptic development. Using morphological and molecular studies in cortical neuronal cultures, we demonstrate that D-serine/SR are associated with PSD-95 and NMDARs in postsynaptic neurons and with glutamatergic synapse stability during synaptic development. Endogenous D-serine and SR colocalize with PSD-95, but not presynaptic vesicular glutamate transporter 1 (VGLUT1), in glutamatergic synapses of cultured cortical neurons. Low-density astrocytes in cortical neuronal cultures lack SR expression but contain enriched D-serine in large vesicle-like structures, suggesting possible synthesis of D-serine in postsynaptic neurons and storage in astrocytes. More interestingly, endogenous D-serine and SR colocalize with PSD-95 in the postsynaptic terminals of glutamatergic synapses during early and late synaptic development, implicating involvement of D-serine/SR in glutamatergic synaptic development. Exogenous application of D-serine enhances the interactions of SR with PSD-95 and NR1, and increases the number of VGLUT1- and PSD-95-positive glutamatergic synapses, suggesting that exogenous D-serine enhances postsynaptic SR/PSD-95 signaling and stabilizes glutamatergic synapses during cortical synaptic development. This is blocked by NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP5) and 7-chlorokynurenic acid (7-CK), a specific antagonist at the glycine site of NMDARs, demonstrating that D-serine effects are mediated through postsynaptic NMDARs. Conversely, exogenous application of glycine has no such effects, suggesting D-serine, rather than glycine, modulates postsynaptic events. Taken together, our findings demonstrate that D-serine/SR are associated with PSD-95 and NMDARs in postsynaptic neurons and with glutamatergic synapse stability during synaptic development, implicating D-serine/SR as regulators of cortical synaptic and circuit development.http://journal.frontiersin.org/Journal/10.3389/fncel.2016.00034/fullAstrocytesd-serineNMDA receptorcortical neuronspostsynapticPSD-95 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hong eLin Ariel A. Jacobi Ariel A. Jacobi Stewart A. Anderson Stewart A. Anderson David R. Lynch David R. Lynch |
spellingShingle |
Hong eLin Ariel A. Jacobi Ariel A. Jacobi Stewart A. Anderson Stewart A. Anderson David R. Lynch David R. Lynch D-serine and serine racemase are associated with PSD-95 and glutamatergic synapse stability Frontiers in Cellular Neuroscience Astrocytes d-serine NMDA receptor cortical neurons postsynaptic PSD-95 |
author_facet |
Hong eLin Ariel A. Jacobi Ariel A. Jacobi Stewart A. Anderson Stewart A. Anderson David R. Lynch David R. Lynch |
author_sort |
Hong eLin |
title |
D-serine and serine racemase are associated with PSD-95 and glutamatergic synapse stability |
title_short |
D-serine and serine racemase are associated with PSD-95 and glutamatergic synapse stability |
title_full |
D-serine and serine racemase are associated with PSD-95 and glutamatergic synapse stability |
title_fullStr |
D-serine and serine racemase are associated with PSD-95 and glutamatergic synapse stability |
title_full_unstemmed |
D-serine and serine racemase are associated with PSD-95 and glutamatergic synapse stability |
title_sort |
d-serine and serine racemase are associated with psd-95 and glutamatergic synapse stability |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cellular Neuroscience |
issn |
1662-5102 |
publishDate |
2016-02-01 |
description |
D-serine is an endogenous coagonist at the glycine site of synaptic NMDA receptors (NMDARs), synthesized by serine racemase (SR) through conversion of L-serine. It is crucial for synaptic plasticity and is implicated in schizophrenia. Our previous studies demonstrated specific loss of SR, D-serine-responsive synaptic NMDARs, and glutamatergic synapses in cortical neurons lacking alpha7 nicotinic acetylcholine receptors, which promotes glutamatergic synapse formation and maturation during development. We thus hypothesize that D-serine and SR (D-serine/SR) are associated with glutamatergic synaptic development. Using morphological and molecular studies in cortical neuronal cultures, we demonstrate that D-serine/SR are associated with PSD-95 and NMDARs in postsynaptic neurons and with glutamatergic synapse stability during synaptic development. Endogenous D-serine and SR colocalize with PSD-95, but not presynaptic vesicular glutamate transporter 1 (VGLUT1), in glutamatergic synapses of cultured cortical neurons. Low-density astrocytes in cortical neuronal cultures lack SR expression but contain enriched D-serine in large vesicle-like structures, suggesting possible synthesis of D-serine in postsynaptic neurons and storage in astrocytes. More interestingly, endogenous D-serine and SR colocalize with PSD-95 in the postsynaptic terminals of glutamatergic synapses during early and late synaptic development, implicating involvement of D-serine/SR in glutamatergic synaptic development. Exogenous application of D-serine enhances the interactions of SR with PSD-95 and NR1, and increases the number of VGLUT1- and PSD-95-positive glutamatergic synapses, suggesting that exogenous D-serine enhances postsynaptic SR/PSD-95 signaling and stabilizes glutamatergic synapses during cortical synaptic development. This is blocked by NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP5) and 7-chlorokynurenic acid (7-CK), a specific antagonist at the glycine site of NMDARs, demonstrating that D-serine effects are mediated through postsynaptic NMDARs. Conversely, exogenous application of glycine has no such effects, suggesting D-serine, rather than glycine, modulates postsynaptic events. Taken together, our findings demonstrate that D-serine/SR are associated with PSD-95 and NMDARs in postsynaptic neurons and with glutamatergic synapse stability during synaptic development, implicating D-serine/SR as regulators of cortical synaptic and circuit development. |
topic |
Astrocytes d-serine NMDA receptor cortical neurons postsynaptic PSD-95 |
url |
http://journal.frontiersin.org/Journal/10.3389/fncel.2016.00034/full |
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