Abstract
BackgroundD-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.Methodology/Principal FindingsNeonatal 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/SignificanceThis 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.
Highlights
Accumulating evidence suggests that hypofunction of glutamatergic neurotransmission via the N-methyl-D-aspartate (NMDA) receptor plays a crucial role in the pathophysiology of schizophrenia [1,2,3,4,5,6]
We found that neonatal administration of MetPhen, an SSR inhibitor, caused behavioral abnormalities, such as increased rearing, and cognitive impairment in juvenile mice and cognitive impairment, and auditory sensory gating prepulse inhibition (PPI) deficits in adult mice
PPI deficits in adult animals with neonatal Met-Phen exposure were improved by a single dose of Dserine, indicating that D-serine could possess antipsychotic activity in this model
Summary
Accumulating evidence suggests that hypofunction of glutamatergic neurotransmission via the N-methyl-D-aspartate (NMDA) receptor plays a crucial role in the pathophysiology of schizophrenia [1,2,3,4,5,6]. Several studies have highlighted evidence suggesting that disturbed NMDA receptor neurotransmission due to decreased D-serine levels, is a causative factor in the pathophysiology of schizophrenia [3,5,6,17,18,19] These findings include firstly, lower levels of D-serine in the blood, cerebrospinal fluid, and postmortem brain tissue from patients with schizophrenia, relative to normal controls [20,21,22,23,24]. Multiple epidemiological surveys support the neurodevelopmental hypothesis for the pathogenesis of schizophrenia [33,34,35] Taken together, these findings point to the possibility that hypofunction of the NMDA receptor, resulting from reduced Dserine levels during gestation could interfere with normal fetal brain neurodevelopment and that these deficits are causative to the onset of schizophrenia in adulthood. 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
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