Blocking miRNA Biogenesis in Adult Forebrain Neurons Enhances Seizure Susceptibility, Fear Memory, and Food Intake by Increasing Neuronal Responsiveness
Blocking miRNA Biogenesis in Adult Forebrain Neurons Enhances Seizure Susceptibility, Fear Memory, and Food Intake by Increasing Neuronal Responsiveness
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DOI：
10.1093/cercor/bhu332
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发表时间：
2016-04-01
期刊：
影响因子：
3.7
通讯作者：
Barco, Angel
中科院分区：
文献类型：
--
作者：
Fiorenza, Anna;Lopez-Atalaya, Jose P.;Barco, Angel
RNase Dicer对于大多数microRNA的成熟至关重要，microRNA是一种在微调基因表达中起重要作用的分子系统。为了从分子水平深入了解Dicer和microRNA系统在脑功能中的作用，我们在可诱导的前脑限制性Dicer 1突变体的海马中进行了2次互补的RNA-seq筛选，旨在分别鉴定主要受Dicer损失影响的microRNA及其靶点。功能基因组学分析预测了与受损microRNA成熟相关的主要生物学过程和表型，包括与microRNA生物学、信号转导、癫痫发作以及突触传递和可塑性相关的类别。与这些预测相一致，我们发现，重组后不久，Dicer缺陷小鼠表现出夸张的癫痫发作反应，增强诱导立即早期基因在不同的刺激，更强和更稳定的恐惧记忆，暴食，并增加兴奋性的CA 1锥体神经元。从长期来看，我们还观察到缓慢和进行性兴奋性神经变性。总的来说，我们的研究结果表明，干扰microRNA生物合成会导致神经元反应性增加，并破坏保护神经元免受过度激活的稳态机制，这可以解释与兴奋性神经元中Dicer丢失相关的初始和晚期表型。
The RNase Dicer is essential for the maturation of most microRNAs, a molecular system that plays an essential role in fine-tuning gene expression. To gain molecular insight into the role of Dicer and the microRNA system in brain function, we conducted 2 complementary RNA-seq screens in the hippocampus of inducible forebrain-restricted Dicer1 mutants aimed at identifying the microRNAs primarily affected by Dicer loss and their targets, respectively. Functional genomics analyses predicted the main biological processes and phenotypes associated with impaired microRNA maturation, including categories related to microRNA biology, signal transduction, seizures, and synaptic transmission and plasticity. Consistent with these predictions, we found that, soon after recombination, Dicer-deficient mice exhibited an exaggerated seizure response, enhanced induction of immediate early genes in response to different stimuli, stronger and more stable fear memory, hyperphagia, and increased excitability of CA1 pyramidal neurons. In the long term, we also observed slow and progressive excitotoxic neurodegeneration. Overall, our results indicate that interfering with microRNA biogenesis causes an increase in neuronal responsiveness and disrupts homeostatic mechanisms that protect the neuron against overactivation, which may explain both the initial and late phenotypes associated with the loss of Dicer in excitatory neurons.