Contribution of NMDA receptor hypofunction in prefrontal and cortical excitatory neurons to schizophrenia-like phenotypes.
Contribution of NMDA receptor hypofunction in prefrontal and cortical excitatory neurons to schizophrenia-like phenotypes.
复制标题
DOI：
10.1371/journal.pone.0061278
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Nakazawa K
中科院分区：
文献类型：
--
作者：
Rompala GR;Zsiros V;Zhang S;Kolata SM;Nakazawa K
药理学和遗传学研究支持 NMDA 受体 (NMDAR) 功能低下在精神分裂症病因中的作用。我们之前已经证明，出生后早期发育过程中皮质边缘中间神经元的 NMDAR 强制亚基 1 (GluN1) 缺失足以赋予小鼠精神分裂症样表型。然而，皮质兴奋性神经元 NMDAR 功能低下的后果尚不清楚。在这里，我们描述了一种条件性基因敲除小鼠品系（CtxGluN1 KO小鼠），其中出生后GluN1缺失主要局限于内侧前额叶皮层和感觉皮层II/III层的兴奋性神经元，原位杂交免疫细胞化学中缺乏GluN1 mRNA表达以及体外记录中缺乏NMDA电流证明了这一点。突变体的听觉惊吓反射的前脉冲抑制以及基于物体的短期记忆均受到损害。然而，他们并没有表现出精神分裂症样表型的其他特征的损害（例如空间工作记忆、社会行为、糖精偏好、新奇和安非他明引起的过度运动以及焦虑相关行为）。此外，在施用 NMDA 受体拮抗剂 MK-801 后，与对照组相比，运动活性没有差异。突变小鼠在长期社会隔离后也表现出可忽略不计的活性氧产生水平，并且对内侧前额叶皮层 II/III 层兴奋性神经元的微型 EPSC/IPSC 的记录表明 GABA 活性没有改变。总而言之，突变小鼠在缺乏反映精神分裂症病理生理学的额外行为或细胞表型的情况下表现出认知缺陷。因此，前额叶和皮质兴奋性神经元中的 NMDAR 功能减退可能仅概括了人类精神分裂症症状的认知方面。
Pharmacological and genetic studies support a role for NMDA receptor (NMDAR) hypofunction in the etiology of schizophrenia. We have previously demonstrated that NMDAR obligatory subunit 1 (GluN1) deletion in corticolimbic interneurons during early postnatal development is sufficient to confer schizophrenia-like phenotypes in mice. However, the consequence of NMDAR hypofunction in cortical excitatory neurons is not well delineated. Here, we characterize a conditional knockout mouse strain (CtxGluN1 KO mice), in which postnatal GluN1 deletion is largely confined to the excitatory neurons in layer II/III of the medial prefrontal cortex and sensory cortices, as evidenced by the lack of GluN1 mRNA expression in in situ hybridization immunocytochemistry as well as the lack of NMDA currents with in vitro recordings. Mutants were impaired in prepulse inhibition of the auditory startle reflex as well as object-based short-term memory. However, they did not exhibit impairments in additional hallmarks of schizophrenia-like phenotypes (e.g. spatial working memory, social behavior, saccharine preference, novelty and amphetamine-induced hyperlocomotion, and anxiety-related behavior). Furthermore, upon administration of the NMDA receptor antagonist, MK-801, there were no differences in locomotor activity versus controls. The mutant mice also showed negligible levels of reactive oxygen species production following chronic social isolation, and recording of miniature-EPSC/IPSCs from layer II/III excitatory neurons in medial prefrontal cortex suggested no alteration in GABAergic activity. All together, the mutant mice displayed cognitive deficits in the absence of additional behavioral or cellular phenotypes reflecting schizophrenia pathophysiology. Thus, NMDAR hypofunction in prefrontal and cortical excitatory neurons may recapitulate only a cognitive aspect of human schizophrenia symptoms.
登录
查看更多内容
影响因子：
3.3
作者：
Gisquet-Verrier, P.;Delatour, B.
通讯作者：
Delatour, B.
影响因子：
64.8
作者：
Iwasato, T;Datwani, A;Itohara, S
通讯作者：
Itohara, S
影响因子：
2.5
作者：
Berretta, N;Jones, RSG
通讯作者：
Jones, RSG
DOI：
10.1073/pnas.0830996100
发表时间：
2003-04-15
影响因子：
11.1
作者：
Fukaya, M;Kato, A;Watanabe, M
通讯作者：
Watanabe, M
影响因子：
2.7
作者：
Dillon, Gregory M.;Qu, Xianlu;Dodart, Jean-Cosme
通讯作者：
Dodart, Jean-Cosme