Histone deacetylases 1 and 2 form a developmental switch that controls excitatory synapse maturation and function.
Histone deacetylases 1 and 2 form a developmental switch that controls excitatory synapse maturation and function.
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DOI：
10.1523/jneurosci.0097-09.2009
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发表时间：
2009-06-24
期刊：
影响因子：
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通讯作者：
Monteggia LM
中科院分区：
文献类型：
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作者：
Akhtar MW;Raingo J;Nelson ED;Montgomery RL;Olson EN;Kavalali ET;Monteggia LM
突触的结构组装可以在一个快速的时间框架内完成，尽管在早期发育过程中形成的大多数新生突触功能不全，对突触前动作电位的反应很差。导致突触成熟延迟的机制尚不清楚。组蛋白去乙酰化酶（HDACs）通过去除组蛋白上的乙酰基来调节染色质的活性状态，抑制基因表达。I类HDAC，包括HDAC 1和HDAC 2，在CNS中表达，尽管它们在神经元功能中的具体作用尚未研究。为了描述HDAC 1和HDAC 2在大脑中的作用，我们使用了HDAC的药理学抑制剂和具有HDAC 1和HDAC 2的条件等位基因的小鼠。我们发现，在早期突触发育过程中，HDAC1和HDAC2的活性降低，会导致兴奋性突触成熟的有力促进和突触数量的适度增加。相比之下，在成熟神经元中，单独HDAC 2水平的降低足以减弱基础兴奋性神经传递，而不会显著改变可检测到的神经末梢的数量。因此，我们建议HDAC1和HDAC2形成一个发育开关，控制突触成熟和功能的方式依赖于神经元网络的成熟状态。
The structural assembly of synapses can be accomplished in a rapid time frame, although most nascent synapses formed during early development are not fully functional and respond poorly to presynaptic action potentials. The mechanisms that are responsible for this delay in synapse maturation are unknown. Histone deacetylases (HDACs) regulate the activity state of chromatin and repress gene expression through the removal of acetyl groups from histones. Class I HDACs, which include HDAC1 and HDAC2, are expressed in the CNS, although their specific role in neuronal function has not been studied. To delineate the contribution of HDAC1 and HDAC2 in the brain, we have used pharmacological inhibitors of HDACs and mice with conditional alleles to HDAC1 and HDAC2. We found that a decrease in the activities of both HDAC1 and HDAC2 during early synaptic development causes a robust facilitation of excitatory synapse maturation and a modest increase in synapse numbers. In contrast, in mature neurons a decrease in HDAC2 levels alone was sufficient to attenuate basal excitatory neurotransmission without a significant change in the numbers of detectable nerve terminals. Therefore, we propose that HDAC1 and HDAC2 form a developmental switch that controls synapse maturation and function acting in a manner dependent on the maturational states of neuronal networks.