Calcyon upregulation in adolescence impairs response inhibition and working memory in adulthood.
Calcyon upregulation in adolescence impairs response inhibition and working memory in adulthood.
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DOI：
10.1038/mp.2011.14
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发表时间：
2011-06
影响因子：
11
通讯作者：
Bergson, C.
中科院分区：
文献类型：
--
作者：
Vazdarjanova, A.;Bunting, K.;Muthusamy, N.;Bergson, C.
钙蛋白调节AMPA谷氨酸受体的活性依赖性内化和兴奋性突触的长期抑制。在精神分裂症患者的大脑中持续观察到钙蛋白水平升高，并且钙蛋白基因与注意缺陷多动障碍相关。执行功能缺陷是常见的两种疾病，至少精神分裂症，病因似乎涉及遗传和神经发育因素。在这里，我们表明钙蛋白过表达CalOE转基因小鼠，终身钙蛋白上调损害执行功能，包括反应抑制和工作记忆，一般不产生学习和记忆缺陷。随着反应抑制和工作记忆以及潜在的神经回路继续成熟到成年早期，我们在出生后28-49天（相当于青春期）功能性沉默了转基因。值得注意的是，在青春期沉默转基因的成年CalOE小鼠中不存在反应抑制和工作记忆缺陷，包括持续行为。在成年期抑制钙蛋白转基因只能部分挽救赤字，这表明在青春期钙蛋白上调不可逆地改变支持成熟反应抑制和工作记忆的神经回路的发展。脑区域免疫印迹显示，海马AMPA GluR 1亚基显著下调，海马和前额叶皮质的CalOE小鼠的GluR 2/3亚基。在青春期沉默转基因可以防止海马GluR 1的减少，进一步暗示在CalOE小鼠中观察到的执行功能缺陷中额海马连接的改变。减轻青少年时期高水平钙蛋白影响的治疗可以预先预防有严重精神疾病风险的个体在执行功能方面的成年缺陷。
Calcyon regulates activity dependent internalization of AMPA glutamate receptors and long term depression of excitatory synapses. Elevated levels of calcyon are consistently observed in brains from schizophrenic patients, and the calcyon gene is associated with attention deficit hyperactivity disorder. Executive function deficits are common to both disorders, and at least for schizophrenia, the etiology appears to involve both heritable and neurodevelopmental factors. Here, we show with calcyon overexpressing CalOE transgenic mice that lifelong calcyon upregulation impairs executive functions including response inhibition and working memory, without producing learning and memory deficits in general. As response inhibition and working memory, as well as the underlying neural circuitry continue to mature into early adulthood, we functionally silenced the transgene during postnatal days 28–49, a period corresponding to adolescence. Remarkably, the response inhibition and working memory deficits including perseverative behavior were absent in adult CalOE mice with the transgene silenced in adolescence. Suppressing the calcyon transgene in adulthood only partially rescued the deficits, suggesting calcyon upregulation in adolescence irreversibly alters development of neural circuits supporting mature response inhibition and working memory. Brain regional immunoblots revealed a prominent down-regulation of AMPA GluR1 subunits in hippocampus, and GluR2/3 subunits in hippocampus and prefrontal cortex of the CalOE mice. Silencing the transgene in adolescence prevented the decrease in hippocampal GluR1, further implicating altered frontohippocampal connectivity in the executive function deficits observed in the CalOE mice. Treatments that mitigate the effects of high levels of calcyon during adolescence could preempt adult deficits in executive functions in individuals at-risk for serious mental illness.
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影响因子：
3.6
作者：
Chen, JS;Kelz, MB;Nestler, EJ
通讯作者：
Nestler, EJ
DOI：
10.1002/ajmg.10148
发表时间：
2002-03-08
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
Ewald, H;Flint, TJ;Kruse, TA
通讯作者：
Kruse, TA
DOI：
10.1002/ajmg.b.30877
发表时间：
2008-12-05
影响因子：
2.8
作者：
DasBanerjee, Tania;Middleton, Frank A.;Berger, David F.;Lombardo, John P.;Sagvolden, Terje;Faraone, Stephen V.
通讯作者：
Faraone, Stephen V.
影响因子：
9.8
作者：
Fallin, MD;Lasseter, VK;Pulver, AE
通讯作者：
Pulver, AE
影响因子：
2
作者：
Farinelli, Missa;Deschaux, Olivier;Garcia, Rene
通讯作者：
Garcia, Rene