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

Darrick T. Balu, Yan Li, Matthew D. Puhl, Michael A. Benneyworth, Alo C. Basu, Shunsuke Takagi, Vadim Y. Bolshakov, Joseph T. Coyle

Research output: Contribution to journalArticlepeer-review

126 Scopus citations

Abstract

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-serinewas necessary for themaintenance 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 changeswere paralleled by diminished BDNF/Akt/mammalian target of rapamycin (mTOR) signaling and impaired performance on a traceconditioning 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.

Original languageEnglish (US)
Pages (from-to)E2400-E2409
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number26
DOIs
StatePublished - Jun 25 2013

Keywords

  • CREB
  • Glycogen synthase 3 kinase
  • MeCP2
  • miR-132

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