@article {Park2021.03.04.434016, author = {Deborah K. Park and Samuel Petshow and Margarita Anisimova and Eden V. Barragan and John A. Gray and Ivar S. Stein and Karen Zito}, title = {Non-ionotropic NMDA receptor signaling alters structural plasticity of dendritic spines in a mouse model for studying schizophrenia}, elocation-id = {2021.03.04.434016}, year = {2021}, doi = {10.1101/2021.03.04.434016}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Schizophrenia is a psychiatric disorder that affects over 20 million people globally. Notably, schizophrenia is associated with decreased density of dendritic spines and decreased levels of D-serine, a co-agonist required for opening of the N-methyl-D-aspartate receptor (NMDAR).Hypofunction of NMDARs is thought to play a role in the pathophysiology of schizophrenia. We hypothesized that the lowered D-serine levels associated with schizophrenia would enhance ion flux-independent signaling by the NMDAR, which drives spine destabilization and loss, and eventually lead to the spine loss associated with schizophrenia. We tested our model using a schizophrenia mouse model lacking the enzyme for D-serine production (serine racemase knock out; SRKO). We show that activity-dependent spine growth is inhibited in SRKO mice of both sexes but can be acutely rescued by exogenous D-serine. When examining a wider range of stimulus strengths, we observed activity-dependent spine growth at higher stimulus strengths, but overall found a strong bias toward spine shrinkage in the SRKO mice as compared to wild-type littermates. We demonstrate that enhanced ion flux-independent signaling through the NMDAR contributes to this bias toward spine shrinkage, which is exacerbated by an increase in synaptic NMDARs in hippocampal synapses of SRKO mice. Our results support a model in which the lowered D-serine levels associated with schizophrenia lead to increased ion flux-independent NMDAR signaling and a bias toward spine shrinkage and destabilization.Significance Statement Schizophrenia is a devastating disorder that is associated with decreased density of dendritic spines. Considering studies that show schizophrenia is also associated with decreased levels of D-serine, a co-agonist required for opening of the N-methyl-D-aspartate receptor (NMDAR), we hypothesized that reduced D-serine levels enhance ion flux-independent (non-ionotropic) NMDAR signaling that then bias spine structural plasticity toward shrinkage and destabilization, and contribute to the spine loss associated with the disorder. Here, we report a role for non-ionotropic NMDAR signaling in driving the destabilization of dendritic spines in conditions of reduced D-serine, offering new insights into the diverse molecular pathways that contribute to spine loss associated with schizophrenia.Competing Interest StatementThe authors have declared no competing interest.}, URL = {https://www.biorxiv.org/content/early/2021/12/03/2021.03.04.434016}, eprint = {https://www.biorxiv.org/content/early/2021/12/03/2021.03.04.434016.full.pdf}, journal = {bioRxiv} }