title: Neonatal disruption of serine racemase causes schizophrenia-like behavioral abnormalities in adulthood: clinical rescue by d-serine.
abstract: BACKGROUND
  D-Serine, an endogenous co-agonist of the N-methyl-D-aspartate (NMDA) receptor, is synthesized from L-serine by serine racemase (SRR). Given the role of D-serine in both neurodevelopment and the pathophysiology of schizophrenia, we examined whether neonatal disruption of D-serine synthesis by SRR inhibition could induce behavioral abnormalities relevant to schizophrenia, in later life.
  
  
  RESULTS
  Neonatal mice (7-9 days) were injected with vehicle or phenazine methosulfate (Met-Phen: 3 mg/kg/day), an SRR inhibitor. Behavioral evaluations, such as spontaneous locomotion, novel object recognition test (NORT), and prepulse inhibition (PPI) were performed at juvenile (5-6 weeks old) and adult (10-12 weeks old) stages. In addition, we tested the effects of D-serine on PPI deficits in adult mice after neonatal Met-Phen exposure. Finally, we assessed whether D-serine could prevent the onset of schizophrenia-like behavior in these mice. Neonatal Met-Phen treatment reduced D-serine levels in the brain, 24 hours after the final dose. Additionally, this treatment caused behavioral abnormalities relevant to prodromal symptoms in juveniles and to schizophrenia in adults. A single dose of D-serine improved PPI deficits in adult mice. Interestingly, chronic administration of D-serine (900 mg/kg/day from P35 to P70) significantly prevented the onset of PPI deficits after neonatal Met-Phen exposure.
  
  
  CONCLUSIONS
  This study shows that disruption of D-serine synthesis during developmental stages leads to behavioral abnormalities relevant to prodromal symptoms and schizophrenia, in later life. Furthermore, early pharmacological intervention with D-serine may prevent the onset of psychosis in adult.
authors: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
authors: Hiroko
authors: H
authors: Hagiwara
authors: Masaomi
authors: M
authors: Iyo
authors: Kenji
authors: K
authors: Hashimoto
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D002531:Cerebellum / Q000378:metabolism; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism; D008124:Locomotion; D008297:Male; D008773:Methylphenazonium Methosulfate; D051379:Mice; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control; D012694:Serine / Q000008:administration & dosage* / Q000378:metabolism; D000099300:Serine Racemase
chemical_list: D014150:Antipsychotic Agents; D008773:Methylphenazonium Methosulfate; D019998:Racemases and Epimerases; D012694:Serine; D000099300:Serine Racemase
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