The Pattern of Cortical Dysfunction in a Mouse Model of a Schizophrenia-Related Microdeletion
The Pattern of Cortical Dysfunction in a Mouse Model of a Schizophrenia-Related Microdeletion
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DOI：
10.1523/jneurosci.1611-13.2013
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发表时间：
2013-09-11
影响因子：
5.3
通讯作者：
Gogos, Joseph A.
中科院分区：
文献类型：
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作者：
Fenelon, Karine;Xu, Bin;Gogos, Joseph A.
我们使用精神分裂症易感22q11.2微缺失的小鼠模型来评估这种遗传病变如何在突触、细胞和分子水平上影响皮质神经回路。在认知缺陷的指导下，我们证明了突变小鼠在高频突触传递和短期可塑性（突触抑制和增强）方面表现出强烈的缺陷，以及长期可塑性和树突棘稳定性的改变。除了先前报道的第5层锥体神经元树突复杂性的减少，突触可塑性的改变发生在相对有限的，往往是微妙的神经元密度和抑制性神经元数量的细胞结构变化的背景下。我们证实了主要micro-RNA加工中明显的DiGeorge关键区8（Dgcr 8）依赖性缺陷，并确定了基因表达和RNA剪接的其他变化，这些变化可能是该突变影响的基础。Dgcr 8水平的降低似乎是前额叶皮层和工作记忆中短期突触可塑性改变的主要驱动因素，但不是长期可塑性和细胞结构的主要驱动因素。我们的研究结果为精神疾病背景下工作记忆障碍的皮层突触和神经元机制提供了信息。他们还提供了深入了解micro-RNA失调与精神分裂症和认知功能障碍的遗传易感性之间的联系。
We used a mouse model of the schizophrenia-predisposing 22q11.2 microdeletion to evaluate how this genetic lesion affects cortical neural circuits at the synaptic, cellular, and molecular levels. Guided by cognitive deficits, we demonstrated that mutant mice display robust deficits in high-frequency synaptic transmission and short-term plasticity (synaptic depression and potentiation), as well as alterations in long-term plasticity and dendritic spine stability. Apart from previously reported reduction in dendritic complexity of layer 5 pyramidal neurons, altered synaptic plasticity occurs in the context of relatively circumscribed and often subtle cytoarchitectural changes in neuronal density and inhibitory neuron numbers. We confirmed the pronounced DiGeorge critical region 8 (Dgcr8)-dependent deficits in primary micro-RNA processing and identified additional changes in gene expression and RNA splicing that may underlie the effects of this mutation. Reduction in Dgcr8 levels appears to be a major driver of altered short-term synaptic plasticity in prefrontal cortex and working memory but not of long-term plasticity and cytoarchitecture. Our findings inform the cortical synaptic and neuronal mechanisms of working memory impairment in the context of psychiatric disorders. They also provide insight into the link between micro-RNA dysregulation and genetic liability to schizophrenia and cognitive dysfunction.