Nuclear Calcium Sensors Reveal that Repetition of Trains of Synaptic Stimuli Boosts Nuclear Calcium Signaling in CA1 Pyramidal Neurons
Nuclear Calcium Sensors Reveal that Repetition of Trains of Synaptic Stimuli Boosts Nuclear Calcium Signaling in CA1 Pyramidal Neurons
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DOI：
10.1016/j.bpj.2010.10.044
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发表时间：
2010-12-15
影响因子：
3.4
通讯作者：
Bading, Hilmar
中科院分区：
文献类型：
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作者：
Bengtson, C. Peter;Freitag, H. Eckehard;Bading, Hilmar
核钙是突触和细胞核之间对话的关键信号，控制持续适应所需的基因组反应，包括记忆和获得性神经保护。核钙瞬变的幅度和持续时间指定活动诱导的转录变化。然而，突触输入和核钙输出之间的精确关系是未知的。在这里，我们使用立体定位交付到大鼠脑的重组腺相关病毒编码核靶向钙传感器，以评估核钙瞬变CA 1锥体神经元刺激后的谢弗侧支。我们发现，在急性海马脑片，突触活动的爆发elerminate一个核钙信号与再生组件在阈值以上的刺激强度。使用经典的刺激范例（即，高频刺激（HFS）和θ脉冲串刺激（TBS））诱导早期LTP（E-LTP）和转录依赖性晚期LTP（L-LTP）的研究中，我们发现，由突触刺激串激活的核钙信号的幅度和动作电位的数量通过它们的重复而大大放大。通过阻断NMDA受体或L型电压门控钙通道，核钙信号和动作电位的产生减少，但不通过导致内部钙库耗尽或阻断代谢型谷氨酸受体的程序。这些研究结果确定了一个重复诱导的开关，在核钙信号与过渡E-LTP到L-LTP，并可能解释为什么转录依赖阶段的L-LTP不是由一个单一的HFS或TBS诱导，但需要重复列车的活动。重组，核靶向的指标可能被证明是有用的，在体内的核钙信号的进一步分析。
Nuclear calcium is a key signal in the dialogue between synapse and nucleus that controls the genomic responses required for persistent adaptations, including memory and acquired neuroprotection. The amplitude and duration of nuclear calcium transients specify activity-induced transcriptional changes. However, the precise relationship between synaptic input and nuclear calcium output is unknown. Here, we used stereotaxic delivery to the rat brain of recombinant adeno-associated viruses encoding nuclear-targeted calcium sensors to assess nuclear calcium transients in CA1 pyramidal neurons after stimulation of the Schaffer collaterals. We show that in acute hippocampal slices, a burst of synaptic activity elicits a nuclear calcium signal with a regenerative component at above-threshold stimulation intensities. Using classical stimulation paradigms (i.e., high-frequency stimulation (HFS) and theta burst stimulation (TBS)) to induce early LTP (E-LTP) and transcription-dependent late LTP (L-LTP), we found that the magnitude of nuclear calcium signals and the number of action potentials activated by synaptic stimulation trains are greatly amplified by their repetition. Nuclear calcium signals and action potential generation were reduced by blockade of either NMDA receptors or L-type voltage-gated calcium channels, but not by procedures that lead to internal calcium store depletion or by blockade of metabotropic glutamate receptors. These findings identify a repetition-induced switch in nuclear calcium signaling that correlates with the transition from E-LTP to L-LTP, and may explain why the transcription-dependent phase of L-LTP is not induced by a single HFS or TBS but requires repeated trains of activity. Recombinant, nuclear-targeted indicators may prove useful for further analysis of nuclear calcium signaling in vivo.