PT  - JOURNAL ARTICLE
AU  - Jonathan M. Wong
AU  - Oluwarotimi Folorunso
AU  - Eden V. Barragan
AU  - Cristina Berciu
AU  - Theresa L. Harvey
AU  - Michael R. DeChellis-Marks
AU  - Jill R. Glausier
AU  - Matthew L. MacDonald
AU  - Joseph T. Coyle
AU  - Darrick T. Balu
AU  - John A. Gray
TI  - Postsynaptic serine racemase regulates NMDA receptor function
AID  - 10.1101/2020.06.16.155572
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.16.155572
4099  - http://biorxiv.org/content/early/2020/06/16/2020.06.16.155572.short
4100  - http://biorxiv.org/content/early/2020/06/16/2020.06.16.155572.full
AB  - 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.Competing Interest StatementJTC reports consulting with Concert Pharm and holding a patent on D-serine for the treatment of serious mental illness, which is owned by Massachusetts General Hospital. DTB served as a consultant for LifeSci Capital and received research support from Takeda Pharmaceuticals. All other authors declare no competing financial interests.