Schizophrenia-Like Dopamine Release Abnormalities in a Mouse Model of NMDA Receptor Hypofunction.
Schizophrenia-Like Dopamine Release Abnormalities in a Mouse Model of NMDA Receptor Hypofunction.
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DOI：
10.1093/schbul/sby003
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发表时间：
2019-01-01
影响因子：
6.6
通讯作者：
Nakazawa K
中科院分区：
文献类型：
--
作者：
Nakao K;Jeevakumar V;Jiang SZ;Fujita Y;Diaz NB;Pretell Annan CA;Eskow Jaunarajs KL;Hashimoto K;Belforte JE;Nakazawa K
苯丙胺诱导的纹状体多巴胺增加及其在前额叶皮质（PFC）的钝释放是精神分裂症病理生理学的标志。虽然N-甲基-D-天冬氨酸受体（NMDAR）功能减退也与精神分裂症有关，但NMDAR功能减退是否导致多巴胺释放异常仍不清楚。我们先前在GABA能神经元特异性NMDAR功能低下突变小鼠中证明了精神分裂症样表型，其中Ppp 1 r2-Cre依赖性缺失不可或缺的NMDAR通道亚基Grin 1在皮质边缘GABA能神经元（包括小清蛋白（PV）阳性神经元）中诱导，在出生后发育，但不在成年期。在这里，我们报告增强多巴胺拟诱导的自发活动，在这些突变体，沿着双向，在体内安非他明诱导的多巴胺释放位点特异性的变化：在出生后Ppp 1 r2-Cre/Grin 1基因敲除（KO）小鼠的多巴胺释放增强，而多巴胺释放显着减少在内侧PFC（mPFC）相比，控制。NAc和mPFC的基底组织多巴胺水平均未受影响。有趣的是，安非他明诱导的c-Fos在多巴胺神经元中的表达的幅度和分布在腹侧被盖区（VTA）的多巴胺能输入亚区的基因型之间是相当的。这些效应似乎是发育和细胞类型特异性调制，因为PV特异性Grin 1 KO小鼠可以诱导与出生后发病的Ppp 1 r2-Cre/Grin 1 KO小鼠相同的效应，但在生长抑素-Cre/Grin 1 KO小鼠或成年发病的Ppp 1 r2-Cre/Grin 1 KO小鼠中未观察到此类异常。这些结果表明，PV GABA能神经元-NMDAR功能减退，在出生后的发展赋予双向NAc超敏和mPFC低敏感性安非他明诱导的多巴胺释放，类似于经典的精神分裂症病理生理学观察。
Amphetamine-induced augmentation of striatal dopamine and its blunted release in prefrontal cortex (PFC) is a hallmark of schizophrenia pathophysiology. Although N-methyl-D-aspartate receptor (NMDAR) hypofunction is also implicated in schizophrenia, it remains unclear whether NMDAR hypofunction leads to dopamine release abnormalities. We previously demonstrated schizophrenia-like phenotypes in GABAergic neuron-specific NMDAR hypofunctional mutant mice, in which Ppp1r2-Cre dependent deletion of indispensable NMDAR channel subunit Grin1 is induced in corticolimbic GABAergic neurons including parvalbumin (PV)-positive neurons, in postnatal development, but not in adulthood. Here, we report enhanced dopaminomimetic-induced locomotor activity in these mutants, along with bidirectional, site-specific changes in in vivo amphetamine-induced dopamine release: nucleus accumbens (NAc) dopamine release was enhanced by amphetamine in postnatal Ppp1r2-Cre/Grin1 knockout (KO) mice, whereas dopamine release was dramatically reduced in the medial PFC (mPFC) compared to controls. Basal tissue dopamine levels in both the NAc and mPFC were unaffected. Interestingly, the magnitude and distribution of amphetamine-induced c-Fos expression in dopamine neurons was comparable between genotypes across dopaminergic input subregions in the ventral tegmental area (VTA). These effects appear to be both developmentally and cell-type specifically modulated, since PV-specific Grin1 KO mice could induce the same effects as seen in postnatal-onset Ppp1r2-Cre/Grin1 KO mice, but no such abnormalities were observed in somatostatin-Cre/Grin1 KO mice or adult-onset Ppp1r2-Cre/Grin1 KO mice. These results suggest that PV GABAergic neuron-NMDAR hypofunction in postnatal development confers bidirectional NAc hyper- and mPFC hypo-sensitivity to amphetamine-induced dopamine release, similar to that classically observed in schizophrenia pathophysiology.
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影响因子：
3.7
作者：
Luo, Yu;Good, Cameron H.;Backman, Cristina M.
通讯作者：
Backman, Cristina M.
影响因子：
6.8
作者：
Eyles, D.;Feldon, J.;Meyer, U.
通讯作者：
Meyer, U.
影响因子：
2.7
作者：
Hertel, P;Mathe, JM;Svensson, TH
通讯作者：
Svensson, TH
影响因子：
9.8
作者：
通讯作者：
--
DOI：
10.1124/jpet.116.235838
发表时间：
2016-10-01
影响因子：
3.5
作者：
Can, Adem;Zanos, Panos;Gould, Todd D.
通讯作者：
Gould, Todd D.