Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 26, Pages E2400-E2409Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1304308110
Keywords
miR-132; MeCP2; glycogen synthase 3 kinase; CREB
Categories
Funding
- National Research Service Award [F32 MH090697]
- Andrew P. Merrill Research Fellowship
- Phyllis AMP
- Jerome Lyle Rappaport Mental Health Research Scholars Award
- National Institutes of Health [R01MH05190, P50MH0G0450]
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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 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.
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