Departments of Physiology and Pharmacology, Anesthesiology, and Neurology, The Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York Health Sciences University, Brooklyn, NY 11203, USA.
Brain Res Bull. 2023 Mar;194:124-127. doi: 10.1016/j.brainresbull.2023.02.001. Epub 2023 Feb 2.
Karim Nader is rightly celebrated for his seminal studies on memory reconsolidation. This commentary celebrates another related contribution - his work on memory maintenance by the autonomously active PKC isoform, PKMζ. There are two methods for "erasing" previously established long-term memory maintenance: 1) inhibiting PKMζ, and 2) blocking reconsolidation. Prior to Nader's research on PKMζ, these two forms of memory erasure were thought to be fundamentally different. Inhibiting PKMζ in a brain region disrupts memory held in storage. But if the inhibitor is injected into the same region immediately after memory retrieval, the drug has no effect. Conversely, inhibiting protein synthesis immediately after memory retrieval blocks reconsolidation. But protein synthesis inhibitors have no effect on memory held in storage without retrieval. The work of Paolo Virginia Migues, Nader, and colleagues, however, revealed an unexpected link between the mechanisms of memory maintenance by PKMζ and the kinase's regulation of postsynaptic AMPAR trafficking that potentiates synaptic transmission and expresses memory during retrieval. This insight led Matteo Bernabo, Nader, and colleagues to observe that memory retrieval first rapidly degrades PKMζ, and then induces the resynthesis of the kinase to restore maintenance of the retrieved memory. This finding explains why a PKMζ inhibitor such as ZIP, if injected in a brain region storing a memory, does not erase the memory immediately after retrieval - the kinase maintaining the retrieved memory has been degraded but not yet resynthesized. Moreover, Bernabo et al. showed that suppressing the resynthesis of PKMζ after its degradation prevents memory reconsolidation, reproducing the effect of general protein synthesis inhibition. Thus, Nader and colleagues demonstrated PKMζ inhibition and reconsolidation blockade disrupt in different ways the same molecular mechanism of memory maintenance - PKMζ inhibition erases all memories maintained in storage by the kinase; reconsolidation blockade disrupts specific recalled memories maintained by PKMζ by preventing resynthesis of the kinase after its degradation.
卡里姆·纳德（Karim Nader）因其在记忆再巩固方面的开创性研究而广受赞誉。这篇评论文章赞扬了他在自主活跃的蛋白激酶 C 同工型 PKMζ维持记忆方面的另一项相关贡献。有两种方法可以“擦除”先前建立的长期记忆维持：1）抑制 PKMζ，2）阻断再巩固。在纳德（Nader）研究 PKMζ 之前，人们认为这两种形式的记忆擦除在根本上是不同的。在大脑区域中抑制 PKMζ会破坏存储中的记忆。但是，如果抑制剂在记忆检索后立即注入同一区域，则药物没有效果。相反，在记忆检索后立即抑制蛋白质合成会阻止再巩固。但是，如果没有检索就没有蛋白质合成抑制剂对存储中的记忆没有影响。但是，Paolo Virginia Migues、纳德（Nader）及其同事的工作揭示了 PKMζ 维持记忆的机制与激酶调节 AMPAR 在后突触中的运输之间的意外联系，这种运输增强了突触传递并在检索时表达了记忆。这一见解促使马特奥·伯纳博（Matteo Bernabo）、纳德（Nader）及其同事观察到，记忆检索首先迅速降解 PKMζ，然后诱导激酶的重新合成以恢复检索到的记忆的维持。这一发现解释了为什么像 ZIP 这样的 PKMζ 抑制剂，如果注入存储记忆的大脑区域，在检索后不会立即擦除记忆-维持检索到的记忆的激酶已经降解但尚未重新合成。此外，伯纳博（Bernabo）等人表明，在降解后抑制 PKMζ 的重新合成可防止记忆再巩固，从而复制了普遍的蛋白质合成抑制的作用。因此，纳德（Nader）及其同事证明，PKMζ 抑制和再巩固阻断以不同的方式破坏了记忆维持的相同分子机制-PKMζ 抑制通过抑制激酶的重新合成来擦除由激酶维持的所有存储中的记忆；再巩固阻断通过阻止降解后激酶的重新合成来破坏由 PKMζ 维持的特定召回记忆。
