title: Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction.
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-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.
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Darrick T
authors.initials: DT
authors.lastname: Balu
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Puhl
authors.forename: Michael A
authors.initials: MA
authors.lastname: Benneyworth
authors.forename: Alo C
authors.initials: AC
authors.lastname: Basu
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Takagi
authors.forename: Vadim Y
authors.initials: VY
authors.lastname: Bolshakov
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Coyle
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials; D006801:Humans; D017774:Long-Term Potentiation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D019998:Racemases and Epimerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020813:Receptor, trkB / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012307:Risk Factors; D012559:Schizophrenia / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D012694:Serine / Q000378:metabolism / Q000627:therapeutic use; D015398:Signal Transduction; D000099300:Serine Racemase
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D035683:MicroRNAs; D019998:Racemases and Epimerases; D020813:Receptor, trkB; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D000099300:Serine Racemase; C546976:MIRN132 microRNA, mouse
keywords: CREB; MeCP2; glycogen synthase 3 kinase; miR-132