Histone Deacetylase 2 Cell Autonomously Suppresses Excitatory and Enhances Inhibitory Synaptic Function in CA1 Pyramidal Neurons
Histone Deacetylase 2 Cell Autonomously Suppresses Excitatory and Enhances Inhibitory Synaptic Function in CA1 Pyramidal Neurons
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DOI：
10.1523/jneurosci.3162-12.2013
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发表时间：
2013-04-03
影响因子：
5.3
通讯作者：
Zhou, Qiang
中科院分区：
文献类型：
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作者：
Hanson, Jesse E.;Deng, Lunbin;Zhou, Qiang
组蛋白去乙酰化酶2（HDAC2）负调节兴奋性突触数量和记忆性能。然而，HDAC2对兴奋性突触的调节是否以细胞自主的方式发生，以及HDAC2是否调节抑制性突触功能还不清楚。为了研究HDAC2功能的这些方面，我们使用大鼠海马切片培养物的稀疏转染和锥体神经元的全细胞记录。单个突触后锥体神经元中HDAC2敲低（KD）增强，而HDAC2过表达（OE）减少兴奋性突触传递。HDAC2的突触后KD也促进了由阈下诱导刺激诱导的长时程增强的表达，而不改变长时程抑制。相反，HDAC2 KD降低，而HDAC2 OE增强，抑制性突触传递。突触后GABA（A）受体（GABA（A）Rs）的改变可能是HDAC 2对抑制性传递影响的基础。与此一致，我们观察到HDAC2 KD后GABA（A）R γ 2亚基的转录和蛋白水平降低，α 2亚基的表面表达降低。此外，我们观察到HDAC 2 KD降低突触而非强直GABA（A）R电流，表明HDAC 2选择性地影响功能性GABA（A）R的突触丰度。对突触后GABA（A）R的免疫染色证实HDAC 2 KD和OE可以调节这些受体的突触丰度。总之，这些结果突出了HDAC2在抑制海马神经元的突触兴奋和增强突触抑制中的作用。因此，突触兴奋相对于抑制的平衡中有利于兴奋的转变可能有助于降低野生型小鼠中HDAC 2功能或抑制认知障碍模型中HDAC的有益作用。
Histone deacetylase 2 (HDAC2) negatively regulates excitatory synapse number and memory performance. However, whether HDAC2 regulation of excitatory synapses occurs in a cell-autonomous manner and whether HDAC2 regulates inhibitory synaptic functions are not well understood. To examine these aspects of HDAC2 function, we used sparse transfection of rat hippocampal slice cultures and whole-cell recordings in pyramidal neurons. HDAC2 knockdown (KD) in single postsynaptic pyramidal neurons enhanced, whereas HDAC2 overexpression (OE) reduced, excitatory synaptic transmission. Postsynaptic KD of HDAC2 also facilitated expression of long-term potentiation induced by subthreshold induction stimuli, without altering long-term depression. In contrast, HDAC2 KD reduced, where as HDAC2 OE enhanced, inhibitory synaptic transmission. Alterations of postsynaptic GABA(A) receptors(GABA(A)Rs) likely underlie the impact of HDAC2 on inhibitory transmission. Consistent with this, we observed reduced transcript and protein levels of the GABA(A)R gamma 2 subunit and reduced surface expression of the alpha 2 subunit after HDAC2 KD. Furthermore, we observed a reduction in synaptic but not tonic GABA(A)R currents by HDAC2 KD, suggesting that HDAC2 selectively affects synaptic abundance of functional GABA(A)Rs. Immunostaining for postsynaptic GABA(A)Rs confirmed that HDAC2 KD and OE can regulate the synaptic abundance of these receptors. Together, these results highlight a role for HDAC2 in suppressing synaptic excitation and enhancing synaptic inhibition of hippocampal neurons. Therefore, a shift in the balance of synaptic excitation versus inhibition favoring excitation could contribute to the beneficial effects of reducing HDAC2 function in wild-type mice or of inhibiting HDACs in models of cognitive impairment.