Volk LJ, Bachman JL, Johnson R, Yu Y, Huganir RL.
PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory.
Nature. 2013 Jan 17;493(7432):420-3.
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Before experiments with the PKM-ζ inhibitor ZIP, there was no evidence that long-term memories were maintained by a specific molecular mechanism. The effect of ZIP on memory is quite specific and unique—memories from one day to three months old are erased, whereas there is no effect on short-term memory, initial learning, or baseline synaptic transmission measured in the living animal (1). Until ZIP, there was no agent known to erase memory long after its consolidation without hampering the ability to acquire new memories later on. So the action of ZIP is not anything like an anesthetic. PKM-ζ increases during memory storage and enhances synaptic transmission (2). PKM-ζ inhibitors also reverse the maintenance of long-term potentiation, again the only agents known to do so (2). Moreover, molecularly jamming the mechanism by which PKM-ζ-mediated synaptic enhancement can be reversed prevents ZIP from erasing memories, strongly supporting that ZIP is working on PKM-ζ (3). All these studies, along with others using additional inhibitors and dominant negative versions of PKM-ζ (4), indicate that PKM-ζ maintains long-term memory in normal animals, from mice to invertebrates such as flies (5) and the mollusk Aplysia (6).
What is new in these two studies is that they use genetically modified mice in which the gene that makes PKM-ζ had been completely deleted at the animals’ conception in order to study learning and memory. They find that the mice’s memory is intact. This is not too surprising because compensation for one gene by another, which might have taken place here but may have escaped detection, is a routine observation in knockout mice. If so, the compensatory gene product would subserve a similar function and exhibit learning-induced upregulation.
So what is the backup mechanism for maintaining memory? The authors do not say, but a clue can be obtained by their observations that ZIP still works to erase memory and reverse long-term potentiation. ZIP is a pseudo-substrate inhibitor of the catalytic domain of atypical PKCs, and effectively inhibits PKM-ζ and the other atypical PKC found in forebrain, PKC-ι/λ. PKC-ι and PKC-λ are different names for the same gene—the human gene is termed PKC-ι and the mouse gene PKC-λ. Before vertebrates, there was only one atypical PKC gene, and a PKM form is made from it (7,8). But with the earliest vertebrates, this function was split into two very closely related atypical PKC genes. In the forebrain, the ζ gene became dedicated to making only PKM-ζ (7), but PKC-ι/λ can also make a PKM form similar to the way it is made in invertebrates—by shortening the PKC-ι/λ protein by proteolysis (8). Genetic studies have shown that these two isoforms can compensate for each other’s functions (9), and both ζ and ι/λ can do the same thing in neurons to enhance excitability (10). We have previously shown that PKC-ι/λ is also activated in LTP (11), and that there is normally a small amount of PKM-ι/λ present in the brain as well (12). The methods in the new papers may not have been optimized to detect synaptic PKM-ι/λ in the complete knockout after learning or LTP. So it is indeed possible that PKC/PKM-ι/λ is the backup mechanism for memory that is normally maintained by PKM-ζ. In such a case, the ability of ZIP to block LTP and memory, reported in the papers, is actually expected and would be strong support for the crucial role of atypical PKCs in maintaining long-term memories.
One of the experiments in one of the papers used a drug that binds to the estrogen receptor in a technique to reduce gene expression of PKM-ζ after a mouse’s initial development, and this is a particularly interesting experiment because they still saw synaptic long-term potentiation. They didn’t look at the mouse’s behavior. However, there was still PKM-ζ around in the brain of the mouse and, more importantly, we don’t know if any new PKM-ζ was made during the LTP from the PKM-ζ mRNA that was still around. Moreover, the estrogen receptor binds to and activates atypical PKC (13), so it is not clear how chronic exposure to the drug they used would affect PKM-ζ or PKC-ι/λ activity or turnover.
So I think future research from these studies will be to try to find the backup mechanisms for memory and to determine what role they play, along with PKM-ζ, in memory in normal animals. I am gratified that our research has stimulated the experiments of others to identify the molecular mechanisms that store long-term memories—one of the fundamental questions in neuroscience.
How does PKMζ maintain long-term memory?.
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