Age-dependent microRNA control of synaptic plasticity in 22q11 deletion syndrome and schizophrenia.
Age-dependent microRNA control of synaptic plasticity in 22q11 deletion syndrome and schizophrenia.
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DOI：
10.1523/jneurosci.1312-12.2012
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发表时间：
2012-10-10
期刊：
影响因子：
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通讯作者：
Zakharenko SS
中科院分区：
文献类型：
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作者：
Earls LR;Fricke RG;Yu J;Berry RB;Baldwin LT;Zakharenko SS
22q11缺失综合征（22q11DS）以多种生理和精神异常为特征，是由22号染色体1.5-3Mb半合子缺失引起的。22q11DS是已知的精神分裂症最大的遗传风险之一；多达30%的22q11DS患者在青春期或成年早期出现精神分裂症。22q11DS小鼠模型显示海马长期增强（LTP）的年龄依赖性增加，LTP是一种突触可塑性形式，是学习和记忆的基础。负责将Ca2+装载到内质网（ER）的sarco（endo）质网Ca2+ atp酶（SERCA2）在该小鼠模型中升高。由此导致的ER Ca2+负荷增加导致神经递质释放增强和LTP增加。然而，22q11微缺失导致SERCA2过表达和LTP增加的机制尚未确定。对多个突变小鼠系的筛选显示，22q11DS疾病关键区域的microRNA （miRNA）生物发生基因Dgcr8的单倍不足导致年龄依赖性突触SERCA2过表达和LTP增加。我们发现SERCA2的调节因子miR-25和miR-185在22q11DS小鼠模型中缺失。在Dgcr8+/−小鼠中，将这些mirna恢复到突触前神经元可以挽救LTP。最后，我们发现SERCA2在精神分裂症患者的大脑中升高，提供了小鼠模型发现与人类疾病之间的联系。我们得出结论，mirna依赖性SERCA2失调是22q11DS和精神分裂症的致病事件。
The 22q11 deletion syndrome (22q11DS) is characterized by multiple physical and psychiatric abnormalities and is caused by the hemizygous deletion of a 1.5–3Mb region of chromosome 22. 22q11DS constitutes one of the strongest known genetic risks for schizophrenia; schizophrenia arises in as many as 30% of patients with 22q11DS during adolescence or early adulthood. A mouse model of 22q11DS displays an age-dependent increase in hippocampal long-term potentiation (LTP), a form of synaptic plasticity underlying learning and memory. The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2), which is responsible for loading Ca2+ into the endoplasmic reticulum (ER), is elevated in this mouse model. The resulting increase in ER Ca2+ load leads to enhanced neurotransmitter release and increased LTP. However, the mechanism by which the 22q11 microdeletion leads to SERCA2 overexpression and LTP increase has not been determined. Screening of multiple mutant mouse lines revealed that haploinsufficiency of Dgcr8, a microRNA (miRNA) biogenesis gene in the 22q11DS disease-critical region, causes age-dependent, synaptic SERCA2 overexpression and increased LTP. We found that miR-25 and miR-185, regulators of SERCA2, are depleted in mouse models of 22q11DS. Restoration of these miRNAs to presynaptic neurons rescues LTP in Dgcr8+/− mice. Finally, we show that SERCA2 is elevated in the brains of patients with schizophrenia, providing a link between mouse model findings and the human disease. We conclude that miRNA-dependent SERCA2 dysregulation is a pathogenic event in 22q11DS and schizophrenia.