Decreased nitrosylation of CaMKII causes aging-associated impairments in memory and synaptic plasticity in mice.
Decreased nitrosylation of CaMKII causes aging-associated impairments in memory and synaptic plasticity in mice.
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DOI：
10.1126/scisignal.ade5892
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发表时间：
2023-07-25
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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CaMKII具有分子记忆功能，因为短暂的Ca 2+刺激可以诱导其突触定位以及Ca 2+非依赖性（自主）活动的持久增加，从而留下超过其持续时间的Ca 2+刺激的记忆痕迹。诱导CaMKII自主性的两种机制的突触效应得到了很好的研究：Thr 286的自磷酸化和与GluN 2B的结合。在这里，我们研究了额外的自主机制的神经元功能：亚硝基化和氧化的CaMKII调节结构域。我们产生了一个基因敲入小鼠品系，其突变使CaMKII调节结构域不能亚硝基化/氧化，CaMKIIΔSNO，并发现它在记忆和突触可塑性方面存在缺陷，与老年野生型小鼠相似。同样类似于老年野生型小鼠，其中CaMKII是亚亚硝基化的，但与其他CaMKII自主机制受损的小鼠不同，CaMKIIΔSNO小鼠在θ爆发刺激（TBS）而不是高频刺激（HFS）诱导时显示出降低的长时程增强（LTP）。与老年野生型小鼠一样，年轻成年CaMKIIΔSNO小鼠的HFS-LTP需要L型电压门控Ca 2+通道。对老年小鼠的影响可能是由亚硝基化的丧失引起的，因为没有检测到CaMKII氧化的下降。在海马神经元，亚硝基化的CaMK II诱导其积累在突触基础条件下的方式介导的GluN 2B结合，LTP刺激后。然而，LTP诱导的突触CaMKII积累不需要亚硝基化。因此，衰老相关的CaMKII亚硝酰化的减少可能会导致慢性突触效应的损害，如基础突触CaMKII的减少。
CaMKII has molecular memory functions, because transient Ca2+-stimuli can induce long-lasting increases in its synaptic localization as well as Ca2+-independent (autonomous) activity, thereby leaving memory traces of Ca2+-stimuli beyond their duration. The synaptic effects of two mechanisms that induce CaMKII autonomy are well studied: autophosphorylation at Thr286 and binding to GluN2B. Here, we examined the neuronal functions of additional autonomy mechanisms: nitrosylation and oxidation of the CaMKII regulatory domain. We generated a knock-in mouse line with mutations that render the CaMKII regulatory domain nitrosylation/oxidation-incompetent, CaMKIIΔSNO, and found that it had deficits in memory and synaptic plasticity that were similar to those in aged wild-type mice. Also similar to aged wild-type mice, in which CaMKII was hypo-nitrosylated, but unlike mice with impairments of other CaMKII autonomy mechanisms, CaMKIIΔSNO mice showed reduced long-term potentiation (LTP) when induced by theta-burst stimulation (TBS) but not high-frequency stimulation (HFS). As in aged wildtype mice, the HFS-LTP in the young adult CaMKIIΔSNO mice required L-type voltage-gated Ca2+-channels. The effects in aged mice were likely caused by the loss of nitrosylation, because no decline in CaMKII oxidation was detected. In hippocampal neurons, nitrosylation of CaMKII induced its accumulation at synapses under basal conditions in a manner mediated by GluN2B binding, like after LTP stimuli. However, LTP-induced synaptic CaMKII accumulation did not require nitrosylation. Thus, an aging-associated decrease in CaMKII nitrosylation may cause impairments by chronic synaptic effects, such as the decrease in basal synaptic CaMKII.
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影响因子：
34.7
作者：
Lisman, John;Yasuda, Ryohei;Raghavachari, Sridhar
通讯作者：
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影响因子：
16.2
作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
Bayer, K Ulrich