Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 26; pp. E2400 - E2409
• Main Authors: Balu, Darrick T, Li, Yan, Puhl, Matthew D, Benneyworth, Michael A, Basu, Alo C, Takagi, Shunsuke, Bolshakov, Vadim Y, Coyle, Joseph T
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.06.2013; National Acad Sciences
• Series: PNAS Plus
• Subjects: Animals; Biological Sciences; Brain; Brain-Derived Neurotrophic Factor - metabolism; Cells; Cognition Disorders - drug therapy; Dendritic Spines - metabolism; Dendritic Spines - pathology; Disease Models, Animal; Excitatory Postsynaptic Potentials; Humans; Long-Term Potentiation; Male; Memory; Mice; Mice, Knockout; MicroRNAs - genetics; MicroRNAs - metabolism; Mutation; Neuronal Plasticity - drug effects; PNAS Plus; Racemases and Epimerases - deficiency; Racemases and Epimerases - genetics; Racemases and Epimerases - metabolism; Receptor, trkB - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Risk assessment; Risk Factors; Rodents; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - etiology; Schizophrenia - metabolism; Serine - metabolism; Serine - therapeutic use; Signal Transduction; MeCP2; glycogen synthase 3 kinase; CREB; miR-132
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1304308110

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.