FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels.
FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels.
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DOI：
10.1016/j.neuron.2012.12.018
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发表时间：
2013-02-20
期刊：
影响因子：
16.2
通讯作者：
Klyachko VA
中科院分区：
文献类型：
--
作者：
Deng PY;Rotman Z;Blundon JA;Cho Y;Cui J;Cavalli V;Zakharenko SS;Klyachko VA
FMRP的缺失会导致脆性X综合征(FXS)，但FMRP的生理功能仍存在很大争议。在这里，我们发现FMRP通过调节动作电位(AP)的持续时间来调节CA3锥体神经元中神经递质的释放。FMRP的缺失导致重复活动中AP过度增宽，突触前钙内流增加，神经递质释放增加。由FMRP缺失引起的AP增宽缺陷具有细胞自主突触前起源，并可在出生后神经元中迅速挽救。FMRP的这些突触前活动是翻译不依赖的，并且通过FMRP与BK通道调节的β4亚单位的相互作用，选择性地由BK通道介导。信息论分析表明，这些FMRP功能的丧失会导致突触信息传递的明显失调。依赖FMRP的AP增宽不仅发生在海马区，也发生在皮质锥体神经元中。因此，我们的结果提示FMRP的主要非翻译依赖突触前功能可能对理解FXS神经病理学有重要意义。
Loss of FMRP causes Fragile X syndrome (FXS), but the physiological functions of FMRP remain highly debatable. Here we show that FMRP regulates neurotransmitter release in CA3 pyramidal neurons by modulating action potential (AP) duration. Loss of FMRP leads to excessive AP broadening during repetitive activity, enhanced presynaptic calcium influx and elevated neurotransmitter release. The AP broadening defects caused by FMRP loss have a cell-autonomous presynaptic origin and can be acutely rescued in postnatal neurons. These presynaptic actions of FMRP are translation-independent and are mediated selectively by BK channels via interaction of FMRP with BK channel’s regulatory β4 subunits. Information-theoretical analysis demonstrates that loss of these FMRP functions causes marked dysregulation of synaptic information transmission. FMRP-dependent AP broadening is not limited to the hippocampus, but also occurs in cortical pyramidal neurons. Our results thus suggest major translation-independent presynaptic functions of FMRP that may have important implications for understanding FXS neuropathology.
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