Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model
Viviane Labrie,Ryutaro Fukumura,Anjali Rastogi,Laura J. Fick,Wei Wang,Paul C. Boutros,James L. Kennedy,Mawahib O. Semeralul,Frankie H. F. Lee,Glen B. Baker,Denise D. Belsham,Steven W. Barger,Yoichi Gondo,Albert H.C. Wong,John C. Roder +14 more
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TLDR
Analysis of SRR genetic variants in humans identified a robust association with schizophrenia and demonstrates that aberrant Srr function and diminished d-serine may contribute to schizophrenia pathogenesis.Abstract:
Abnormal N-methyl-d-aspartate receptor (NMDAR) function has been implicated in the pathophysiology of schizophrenia. d-serine is an important NMDAR modulator, and to elucidate the role of the d-serine synthesis enzyme serine racemase (Srr) in schizophrenia, we identified and characterized mice with an ENU-induced mutation that results in a complete loss of Srr activity and dramatically reduced d-serine levels. Mutant mice displayed behaviors relevant to schizophrenia, including impairments in prepulse inhibition, sociability and spatial discrimination. Behavioral deficits were exacerbated by an NMDAR antagonist and ameliorated by d-serine or the atypical antipsychotic clozapine. Expression profiling revealed that the Srr mutation influenced several genes that have been linked to schizophrenia and cognitive ability. Transcript levels altered by the Srr mutation were also normalized by d-serine or clozapine treatment. Furthermore, analysis of SRR genetic variants in humans identified a robust association with schizophrenia. This study demonstrates that aberrant Srr function and diminished d-serine may contribute to schizophrenia pathogenesis.read more
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N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia?
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Contribution of the d-Serine-Dependent Pathway to the Cellular Mechanisms Underlying Cognitive Aging.
Brigitte Potier,Fabrice R. Turpin,Pierre-Marie Sinet,Emilie Rouaud,Jean-Pierre Mothet,Catherine Videau,Jacques Epelbaum,Patrick Dutar,Jean-Marie Billard +8 more
TL;DR: It is shown that an impaired activation of the strychnine-insensitive glycine site of N-methyl-d-aspartate receptors (NMDA-R) by its agonist d-serine contributes to deficits of synaptic plasticity in the hippocampus of memory-impaired aged rats.
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Glial D-Serine Gates NMDA Receptors at Excitatory Synapses in Prefrontal Cortex
Pascal Fossat,Pascal Fossat,Fabrice R. Turpin,Fabrice R. Turpin,Silvia Sacchi,Jérôme Dulong,Jérôme Dulong,Ting Shi,J M Rivet,Jonathan V. Sweedler,Loredano Pollegioni,Millan Mark,Stéphane H. R. Oliet,Stéphane H. R. Oliet,Jean-Pierre Mothet,Jean-Pierre Mothet +15 more
TL;DR: It is demonstrated that under the present conditions, D-ser is the principle endogenous coagonist of synaptic NMDARs at mature excitatory synapses in layers V/VI of mPFC where it is essential for long-term potentiation (LTP) induction.
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The neurobiology of D -amino acid oxidase and its involvement in schizophrenia
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