Department of Neurology, Georgia Health Sciences University, Augusta, GA, USA.
Mol Psychiatry. 2011 Jun;16(6):672-84. doi: 10.1038/mp.2011.14. Epub 2011 Mar 15.
Calcyon regulates activity-dependent internalization of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (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 Cal(OE) 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 Cal(OE) 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 downregulation of AMPA GluR1 subunits in hippocampus and GluR2/3 subunits in hippocampus and prefrontal cortex of the Cal(OE) mice. Silencing the transgene in adolescence prevented the decrease in hippocampal GluR1, further implicating altered fronto-hippocampal connectivity in the executive function deficits observed in the Cal(OE) 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.
钙调蛋白调节 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）谷氨酸受体的活性依赖性内吞作用和兴奋性突触的长时程抑制。精神分裂症患者的大脑中始终观察到钙调蛋白水平升高，钙调蛋白基因与注意缺陷多动障碍有关。执行功能缺陷在这两种疾病中都很常见，至少对于精神分裂症，其病因似乎涉及遗传和神经发育因素。在这里，我们通过钙调蛋白过表达 Cal(OE)转基因小鼠表明，终生钙调蛋白上调会损害执行功能，包括反应抑制和工作记忆，而不会导致一般的学习和记忆缺陷。由于反应抑制和工作记忆以及潜在的神经回路在成年早期仍在继续成熟，我们在出生后第 28-49 天期间（对应青春期）对转基因进行了功能沉默。值得注意的是，在青春期沉默转基因的成年 Cal(OE)小鼠中，反应抑制和工作记忆缺陷（包括持续行为）消失了。在成年期抑制钙调蛋白转基因仅部分挽救了这些缺陷，表明青春期钙调蛋白上调不可逆地改变了支持成熟反应抑制和工作记忆的神经回路发育。大脑区域免疫印迹显示海马体中 AMPA GluR1 亚基和海马体和前额叶皮层中 GluR2/3 亚基的显著下调。在青春期沉默转基因可防止海马体 GluR1 的减少，进一步表明在 Cal(OE)小鼠中观察到的执行功能缺陷与额-海马连接改变有关。在青春期减轻钙调蛋白高表达影响的治疗方法可能会预防有严重精神疾病风险的个体成年期执行功能缺陷。
