| First Author | Park DK | Year | 2022 |
| Journal | Neurobiol Dis | Volume | 170 |
| Pages | 105772 | PubMed ID | 35605760 |
| Mgi Jnum | J:326837 | Mgi Id | MGI:7311434 |
| Doi | 10.1016/j.nbd.2022.105772 | Citation | Park DK, et al. (2022) Reduced d-serine levels drive enhanced non-ionotropic NMDA receptor signaling and destabilization of dendritic spines in a mouse model for studying schizophrenia. Neurobiol Dis 170:105772 |
| abstractText | 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). We hypothesized that lowered d-serine levels associated with schizophrenia would enhance ion flux-independent signaling by the NMDAR, driving destabilization and loss of dendritic spines. We tested our hypothesis using the serine racemase knockout (SRKO) mouse model, which lacks the enzyme for d-serine production. We show that activity-dependent spine growth is impaired in SRKO mice, but can be acutely rescued by exogenous d-serine. Moreover, we find a significant bias of synaptic plasticity toward spine shrinkage in the SRKO mice as compared to wild-type littermates. Notably, we demonstrate that enhanced ion flux-independent signaling through the NMDAR contributes to this bias toward spine destabilization, which is exacerbated by an increase in synaptic NMDARs in hippocampal synapses of SRKO mice. Our results support a model in which lowered d-serine levels associated with schizophrenia enhance ion flux-independent NMDAR signaling and bias toward spine shrinkage and destabilization. |
