Increased excitation-inhibition balance and a loss of GABAergic synapses in the serine racemase knockout model of NMDA receptor hypofunction

Congrats to Shekib for his first Gray Lab publication! There is substantial evidence that both NMDA receptor (NMDAR) hypofunction and dysfunction of GABAergic neurotransmission contribute to schizophrenia, though the relationship between these pathophysiological processes remains poorly understood. Here, we used the serine racemase knockout (SRKO) mice, a model of reduced NMDAR activity in which there is a >90% reduction in the NMDAR co-agonist D-serine. Our results, published in the Journal of Neurophysiology, show a significant reduction in inhibitory synapses onto CA1 pyramidal neurons in the SRKO mice. Using a single-neuron genetic deletion approach, we also found a cell-autonomous loss GABAergic synapses onto pyramidal neurons following SR deletion. These results support a model whereby NMDAR hypofunction in pyramidal cells disrupts GABAergic synapse development leading to disrupted feedback inhibition and impaired neuronal synchrony. Congrats to Shekib Jami and Jon Wong, and thank you to Scott and Emily from Kim McAllister’s lab for the immunohistochemical confirmation of our electrophysiological findings.

Postsynaptic serine racemase regulates NMDA receptor function

Congrats to Jon Wong for his first-author publication in the Journal of Neuroscience – and the cover of the final ever print issue! D-serine is the primary NMDA receptor (NMDAR) co-agonist at mature forebrain synapses and is synthesized by the enzyme serine racemase (SR) in neurons, though the localization of D-serine release is unknown. Here we show that SR is postsynaptic and, using a single-neuron genetic approach in SR conditional knockout mice, we demonstrate that postsynaptic SR regulates synaptic NMDAR function in the hippocampus. These 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. Thanks to Timi Folorunso, Darrick Balu, and Joe Coyle for their major contributions and input on this project.

First Gray Lab graduate! Dr. Jon Wong

Biggest congratulations to new Ph.D. recipient Jon Wong who presented his dissertation exit seminar today. Unfortunately it had to be over Zoom due to COVID-19 so we could not all celebrate in person, but Jon did a great job. Hope I didn’t roast him too much in my intro!

I was so fortunate to have Jon as my first graduate student – he brought his intelligence and diligence and was an amazing teacher and mentor to the others in the lab.

Jon actually joined my lab before my lab was built, so we went through some growing pains together, but he stuck with it and wrote a beautiful dissertation “Electrophysiological Characterization of NMDA Receptor Modulation by its Co-Agonists.”  Congrats Dr. Wong!

 

Postsynaptic serine racemase regulates NMDA receptor function – BioRxiv Preprint

D-serine is the primary NMDA receptor (NMDAR) co-agonist at mature forebrain synapses and is synthesized by the enzyme serine racemase (SR) in neurons, though the localization of D-serine release is unknown. Here, we show that SR is postsynaptic and, using a single-neuron genetic approach in SR conditional knockout mice, we demonstrate that postsynaptic SR regulates synaptic NMDAR function in the hippocampus. These 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. Congrats to Jon Wong! Thanks to Timi Folorunso, Darrick Balu, and Joe Coyle for their major contributions and input on this project.

Welcome Hannah Saeger

The Gray Lab welcomes Hannah Saeger who rotating in the lab from the Pharmacology/Toxicology graduate group.  She graduated from UC Santa Cruz where she worked in a C. elegans laboratory examining the regulation of gene expression during development, specifically the role of various transcription factors in spermatogenesis. She is likely going to join the lab of collaborator David Olson, so is going to learn patch-clamp electrophysiology in my lab that will hopefully assist her in her future studies of psychedelic action. Welcome Hannah!

PP1 dephosphorylates GluN2B in the PDZ ligand to regulate synaptic NMDA receptor content

In this ongoing collaboration with Antonio Sanz-Clemente at Northwestern University, we define an additional mechanism regulating the synaptic expression of the GluN2B subunit of NMDA receptors.  Following synaptic activity, the GluN2B subunit is phosphorylated on the C-terminal PDZ ligand at S1480 but casein kinase 2 (CK2) resulting in the removal of GluN2B from the synapse. We now show that these extrasynaptic GluN2B subunits are dephosphorylated by PP1 in an activity-dependent manner resulting in the re-entry into the synapse.

See our paper at Cell Reports: https://doi.org/10.1016/j.celrep.2019.06.030

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