Differential effects of alphaCaMKII mutation on hippocampal learning and changes in intrinsic neuronal excitability.
Differential effects of alphaCaMKII mutation on hippocampal learning and changes in intrinsic neuronal excitability.
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αCaMKII 突变对海马学习和内在神经元兴奋性变化的不同影响。
DOI：
10.1111/j.1460-9568.2006.04746.x
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Disterhoft,JohnF
中科院分区：
文献类型：
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作者：
Ohno,Masuo;Sametsky,EvgenyA;Silva,AlcinoJ;Disterhoft,JohnF
α -钙/钙调素依赖性激酶II （α camkii）是突触可塑性的核心，但尚不清楚这种激酶是否有助于神经元兴奋性变化，这是细胞学习相关的。通过敲入T286A靶向突变阻止αCaMKII自磷酸化（αCaMKIIT286A）的小鼠，我们研究了αCaMKII信号在Morris水迷宫中海马依赖性空间学习过程中调节海马神经元兴奋性的作用。野生型对照小鼠在水迷宫空间训练后，CA1锥体神经元的兴奋性增加，这是通过脉冲后超极化（AHP）的减少来评估的。重要的是，当野生型小鼠暴露在没有逃脱平台的水迷宫中，并且与训练小鼠（游泳对照组）游泳相同的时间时，它们没有表现出AHP的变化，因此表现出与空间训练相关的海马CA1兴奋性的学习特异性增加。同时，αCaMKIIT286Amice在水迷宫训练后表现出空间学习障碍，但AHP水平下降，与野生型对照组相似。值得注意的是，αCaMKIIT286Amutants的训练组和游泳对照组均表现出相似的兴奋性增加，这表明在缺乏正常αCaMKII功能的情况下，游泳本身足以诱导兴奋性的变化。这一结果表明，αCaMKII -独立性的神经元兴奋性变化与学习和突触可塑性机制的分离，表明兴奋性类型的增加与学习并不完全相关。我们的研究结果表明，αCaMKII信号可能在训练过程中抑制与学习无关的变化，从而使海马CA1神经元适当地增加编码空间记忆的兴奋性。
α‐Calcium/calmodulin‐dependent kinase II (αCaMKII) is central to synaptic plasticity but it remains unclear whether this kinase contributes to neuronal excitability changes, which are a cellular correlate of learning. Using knock‐in mice with a targeted T286A mutation that prevents the autophosphorylation of αCaMKII (αCaMKIIT286A), we studied the role of αCaMKII signaling in regulating hippocampal neuronal excitability during hippocampus‐dependent spatial learning in the Morris water maze. Wild‐type control mice showed increased excitability of CA1 pyramidal neurons, as assessed by a reduction in the postburst afterhyperpolarization (AHP), after spatial training in the water maze. Importantly, wild‐type mice did not show AHP changes when they were exposed to the water maze without the escape platform and swam the same amount of time as the trained mice (swim controls), thus manifesting learning‐specific increases in hippocampal CA1 excitability associated with spatial training. Meanwhile, αCaMKIIT286Amice showed impairments in spatial learning but exhibited reduced levels of AHP that were similar to wild‐type controls after water‐maze training. Notably, both trained and swim‐control groups of αCaMKIIT286Amutants showed similar increased excitability, indicating that swimming by itself is enough to induce changes in excitability in the absence of normal αCaMKII function. This result demonstrates dissociation of αCaMKII‐independent changes in intrinsic neuron excitability from learning and synaptic plasticity mechanisms, suggesting that increases in excitabilityper seare not perfectly correlated with learning. Our findings suggest that αCaMKII signaling may function to suppress learning‐unrelated changes during training, thereby allowing hippocampal CA1 neurons to increase their excitability appropriately for encoding spatial memories.