The enzyme protein kinase M-ζ (PKM-ζ) was thought to be a fixture of long-term memory, as its inhibition could erase old memories, whilst adding it could strengthen faded ones. Two independent groups have challenged the role of this memory molecule by developing mice that completely lack it and show no detectable memory problems.

The scientists published their findings in the journal Nature¹ ². Back in 2007, Todd Sacktor was able to wipe out month-old memories of unpleasant smells in rats by injecting their brains with ZIP, a peptide that was meant to block PKM-ζ. Other teams obtained similar results, erasing different kinds of memory by injecting ZIP into the brains of rodents, flies and sea slugs. In 2011, Sacktor was able to strengthen the memory of unpleasant tastes in rats by injecting their brains with viruses carrying extra copies of PKM-ζ.

These studies suggested that long-term memory was fragile and depended on the continuous activity of a single enzyme. Much of this data depended on the actions of ZIP. Richard Huganir of John Hopkins University in Baltimore, Maryland, deleted two genes in embryonic mice, one for PKM-ζ and one for PKC-ζ. Robert Messing and his colleagues at the University of California in San Francisco obtained similar results.

Neither of these groups of mice showed any problems with their memory. Messing’s mice formed persistent memories for fears, objects, places and movements in behavioral tests. Huganir’s mice showed normal levels of long-term potentiation, the strengthening of synapses between two neurons. This is linked to learning and memory.

Our study conclusively says that PKM-ζ doesn’t regulate memory, states Huganir. Surprisingly, both teams found that ZIP could still disrupt established memories in their mice, despite the lack of PKM-ζ. Lenora Volk, part of Huganir’s team, states that their study doesn’t rule out the possibility that PKM-ζ plays a role in some forms of memory, but it’s not the essential master regulator of memory that the literature suggests.

Sacktor thinks that a different gene might compensate for the loss, which is something that routinely happens in mice that have had some genes deleted. Sacktor says that the proteins PKM-ι or PKM-λ may be involved.

Huganir’s team created mice whose PKM-ζ gene could be deleted by giving them a specific drug. This allowed them to deplete the enzyme during adulthood, after the mice had grown up with normal levels. These animals still showed normal long-term potentiation.