Prolonged Ketamine Effects in Sp4 Hypomorphic Mice: Mimicking Phenotypes of Schizophrenia.
Prolonged Ketamine Effects in Sp4 Hypomorphic Mice: Mimicking Phenotypes of Schizophrenia.
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DOI：
10.1371/journal.pone.0066327
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zhou X
中科院分区：
文献类型：
--
作者：
Ji B;Wang X;Pinto-Duarte A;Kim M;Caldwell S;Young JW;Behrens MM;Sejnowski TJ;Geyer MA;Zhou X
已经证实，精神分裂症患者对NMDAR拮抗剂的反应表现为NMDAR功能受损和症状加重。NMDAR信号的异常可能导致认知缺陷，这在很大程度上导致精神分裂症的功能残疾。建立小鼠遗传模型将有助于研究精神分裂症低谷氨酸能神经传递的分子机制。在这里，我们研究了SP4缺陷症小鼠对NMDAR拮抗剂的脑电和各种行为范式的反应。SP4缺陷症小鼠对NMDAR拮抗剂的敏感性增加，对NMDAR拮抗剂的反应延长。此前有报道称，SP4亚型小鼠减少了NMDAR1的表达，减少了CA1区LTP的缺失。分子研究表明，谷氨酸脱羧酶67(GAD67)在大脑皮质和海马区的表达减少，这与SP4基因缺陷小鼠的异常伽马振荡一致。另一方面，有报道称人类SP4基因在精神分裂症中缺失。几项人类遗传学研究表明，SP4基因与精神分裂症和其他精神疾病有关。因此，阐明SP4亚型小鼠的SP4分子通路可能为我们理解精神分裂症中异常的NMDAR信号提供新的见解。
It has been well established that schizophrenia patients display impaired NMDA receptor (NMDAR) functions as well as exacerbation of symptoms in response to NMDAR antagonists. Abnormal NMDAR signaling presumably contributes to cognitive deficits which substantially contribute to functional disability in schizophrenia. Establishing a mouse genetic model will help investigate molecular mechanisms of hypoglutmatergic neurotransmission in schizophrenia. Here, we examined the responses of Sp4 hypomorphic mice to NMDAR antagonists in electroencephalography and various behavioral paradigms. Sp4 hypomorphic mice, previously reported to have reduced NMDAR1 expression and LTP deficit in hippocampal CA1, displayed increased sensitivity and prolonged responses to NMDAR antagonists. Molecular studies demonstrated reduced expression of glutamic acid decarboxylase 67 (GAD67) in both cortex and hippocampus, consistent with abnormal gamma oscillations in Sp4 hypomorphic mice. On the other hand, human SP4 gene was reported to be deleted in schizophrenia. Several human genetic studies suggested the association of SP4 gene with schizophrenia and other psychiatric disorders. Therefore, elucidation of the Sp4 molecular pathway in Sp4 hypomorphic mice may provide novel insights to our understanding of abnormal NMDAR signaling in schizophrenia.
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影响因子：
3.3
作者：
Ehrlichman, R. S.;Gandal, M. J.;Siegel, S. J.
通讯作者：
Siegel, S. J.
影响因子：
5.3
作者：
Adams, B;Moghaddam, B
通讯作者：
Moghaddam, B
影响因子：
48
作者：
Dalmau, Josep;Gleichman, Amy J.;Hughes, Ethen G.;Rossi, Jeffrey E.;Peng, Xiaoyu;Lai, Meizan;Dessain, Scott K.;Rosenfeld, Mynna R.;Balice-Gordon, Rita;Lynch, David R.
通讯作者：
Lynch, David R.
影响因子：
7.6
作者：
LAHTI, AC;KOFFEL, B;TAMMINGA, CA
通讯作者：
TAMMINGA, CA
影响因子：
9.8
作者：
Blackwood, DHR;Fordyce, A;Muir, WJ
通讯作者：
Muir, WJ