Neonatal disruption of serine racemase causes schizophrenia-like behavioral abnormalities in adulthood: clinical rescue by d-serine.
Neonatal disruption of serine racemase causes schizophrenia-like behavioral abnormalities in adulthood: clinical rescue by d-serine.
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DOI：
10.1371/journal.pone.0062438
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hashimoto K
中科院分区：
文献类型：
--
作者：
Hagiwara H;Iyo M;Hashimoto K
d -丝氨酸是n -甲基- d -天冬氨酸（NMDA）受体的内源性协同激动剂，由l-丝氨酸通过丝氨酸消旋酶（SRR）合成。考虑到d -丝氨酸在神经发育和精神分裂症病理生理中的作用，我们研究了新生儿通过SRR抑制d -丝氨酸合成的中断是否会在以后的生活中诱发与精神分裂症相关的行为异常。新生小鼠（7-9天）注射SRR抑制剂芬那嗪（Met-Phen: 3mg /kg/day）。在幼年期（5-6周龄）和成年期（10-12周龄）分别进行自主运动、新目标识别测试（NORT）和预脉冲抑制（PPI）等行为评价。此外，我们测试了d -丝氨酸对成年小鼠在新生儿接触甲基苯胺后PPI缺陷的影响。最后，我们评估了d -丝氨酸是否可以预防这些小鼠出现精神分裂症样行为。新生儿在最后一次给药24小时后，Met-Phen治疗降低了大脑中的d -丝氨酸水平。此外，这种治疗还会导致青少年前驱症状和成人精神分裂症相关的行为异常。单剂量d -丝氨酸可改善成年小鼠的PPI缺陷。有趣的是，长期给药d -丝氨酸（900 mg/kg/天，从P35到P70）可以显著预防新生儿接触甲基苯后PPI缺陷的发生。这项研究表明，发育阶段d -丝氨酸合成的中断会导致与前驱症状和精神分裂症相关的行为异常，在以后的生活中。此外，用d -丝氨酸进行早期药物干预可以预防成人精神病的发生。
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. 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. 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.
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DOI：
10.1176/appi.ajp.2011.10081209
发表时间：
2011-08
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Carrión RE;Goldberg TE;McLaughlin D;Auther AM;Correll CU;Cornblatt BA
通讯作者：
Cornblatt BA
影响因子：
11
作者：
Basu, A. C.;Tsai, G. E.;Coyle, J. T.
通讯作者：
Coyle, J. T.
影响因子：
1.8
作者：
Fukushima, T;Kawai, J;Toyo'oka, T
通讯作者：
Toyo'oka, T
影响因子：
10.6
作者：
Hashimoto, Kenji;Ishima, Tamaki;Iyo, Masaomi
通讯作者：
Iyo, Masaomi
影响因子：
--
作者：
Hashimoto, Kenji;Shimizu, Eiji;Iyo, Masaomi
通讯作者：
Iyo, Masaomi