Gray Lab

Congrats to Eden for her finally published dissertation work! And thank you to the labs of Karen Zito and Kim Dore for their crucial contributions to making this such a robust story.

NMDARs have been found to drive synaptic plasticity via non-ionotropic (ion flux-independent) signaling upon the binding of glutamate in the absence of co-agonist, though conflicting results have led to controversy. Here, we found that D-serine inhibits non-ionotropic NMDAR-mediated long-term depression (LTD) and LTD-associated spine shrinkage. Thus, the developmental regulation of D-serine is likely a determinant of non-ionotropic NMDAR plasticity during critical periods of plasticity. In addition, these findings suggest that a major source of the contradictory findings among labs might be attributed to experimental variability in D-serine availability.

Excited to announce the launch of the UC Davis Institute for Psychedelics and Neurotherapeutics

Announcement: https://www.ucdavis.edu/health/news/uc-davis-establishes-institute-psychedelics-and-neurotherapeutics 

Website: https://neurotherapeutics.ucdavis.edu/ 

Huge congrats to Eden Barragan who presented her dissertation exit seminar today entitled “D-serine is a Determinant of Non-Ionotropic LTD” on a project that she initiated during the COVID19 pandemic with some incredibly cool results we cannot wait to share.  I am so proud of everything Eden has accomplished in the lab and for her amazing perseverance through both the pandemic and some experimental bad luck.  Congrats Dr. Barragan!

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.

I enjoyed giving a virtual public talk at NeuroFest 2021 entitled: “Reversing Synapse Dysfunction in Neuropsychiatric Disease”
Watch it here, my talk begins at 38:15

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.

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!

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.

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!