2013/05/31 by Darrick T. Balu, Yan Li, Matthew D. Puhl +5 · 3 citations
Biochemistry, Genetics and Molecular Biology · Neuroscience · Psychology · Medicine · #Amino Acid Enzymes and Metabolism #Tryptophan and brain disorders #Neuroscience and Neuropharmacology Research #Neurochemical #NMDA receptor #Neuropathology #Schizophrenia (object-oriented programming) #Neuroscience #Hippocampal formation #Psychology #Cognition #Neurodegeneration #Knockout mouse #Medicine #Receptor #Internal medicine #Psychiatry #Disease
paper · pdf · doi:10.1073/pnas.1304308110
openalex publication_date 2013/05/31 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/02
Schizophrenia is characterized by reduced hippocampal volume, decreased dendritic spine density, altered neuroplasticity signaling pathways, and cognitive deficits associated with impaired hippocampal function. We sought to determine whether this diverse pathology could be linked to NMDA receptor (NMDAR) hypofunction, and thus used the serine racemase-null mutant mouse (SR(-/-)), which has less than 10% of normal brain D-serine, an NMDAR coagonist. We found that D-serine was necessary for the maintenance of long-term potentiation in the adult hippocampal dentate gyrus and for full NMDAR activity on granule cells. SR(-/-) mice had reduced dendritic spines and hippocampal volume. These morphological changes were paralleled by diminished BDNF/Akt/mammalian target of rapamycin (mTOR) signaling and impaired performance on a trace-conditioning memory task. Chronic D-serine treatment normalized the electrophysiological, neurochemical, and cognitive deficits in SR(-/-) mice. These results demonstrate that NMDAR hypofunction can reproduce the numerous hippocampal deficits associated with schizophrenia, which can be reversed by chronic peripheral D-serine treatment.