The Amnesia Drug: Frightening but Interesting

We tend to think of memories in the brain once they are consolidated as relatively stable things. For example, you don't tend to think of any active biochemical process being necessary to maintain long-term memories. This is almost an intuitive conclusion: wouldn't any active process required for memory maintenance be eventually disrupted if expected to operate over a long period? Further, we know that it forgetting is an active rather than a passive process -- such as in fear extinction where activity in certain parts of the brain is necessary to successfully "forget" the fear.

However, research on a protein called PKCzeta has turned this all on its head. Researchers have shown that inhibitors to this enzyme can cause the animal to forget long-term memories learned weeks earlier:

Many substances interfere with memory, as any hung-over partygoer can attest. But although booze and drugs can disrupt the making of new memories (such as the embarrassing antics at last night's party), they leave older memories intact. Neuroscientists think this is because, after a time, memories become wired into the brain in a way that makes them harder to wipe out: Long-term memories, in the generally accepted view, are maintained by structural changes to the synaptic connections between neurons.

A study on page 951 adds to other recent evidence that may challenge, or at least complicate, this view. A team of neuroscientists reports that injecting a drug that blocks an enzyme called protein kinase Mzeta (PKMzeta) into the cerebral cortex of rats makes the animals forget a meal that made them sick weeks earlier. The findings suggest that the continuing activity of PKMzeta is somehow necessary to maintain long-term memory, something that's not predicted by most current hypotheses on the mechanisms of memory. The work also hints at the possibility of future drugs that could tinker with memory--for therapeutic uses or for boosting brainpower.

"This is a somewhat mind-blowing conclusion," says David Glanzman, a neuroscientist at the University of California, Los Angeles. Enzymes similar to PKMzeta are known to be important in early stages of memory formation, Glanzman says, but most researchers had thought that these compounds were not needed to sustain memory once synaptic changes--such as the growth of new synapses or the strengthening of existing ones--had occurred.

In the new study, Todd Sacktor of State University of New York Downstate Medical Center in Brooklyn and Reut Shema and Yadin Dudai of the Weizmann Institute of Science in Rehovot, Israel, first gave rats an unsavory meal to remember. They added a novel taste, saccharin, to the rodents' drinking water, then 40 minutes later gave a nausea-inducing injection of lithium. Rats normally avoid saccharin-laced water for weeks after such an experience. But in the days that followed, when the researchers injected the PKMzeta-blocking drug, called ZIP, into the insular cortex, where taste memories are thought to reside, rats lost their aversion to saccharin within 2 hours and did not recover it in the 25-day study period. Moreover, giving the injection up to 25 days after the nauseating meal erased the aversion. Yet when given prior to saccharin exposure, ZIP had no effect on the ability to form new memories--the rats still learned to avoid the flavored water.

This last part about the drug ZIP is both scary and fascinating.

It's scary because I am one dose of ZIP away from wasting a whole lotta time in school. It is basically a drug that causes amnesia. I guess I could see how it might have some appealing therapeutic uses such as forgetting traumatic memories, but it is still far from clear how you could use it at all selectively. (Furthermore, I am a bit curious to see a full inventory of what types of memories are susceptible to this type of erasure. For example, are procedural memories in the cerebellum?) At present, this isn't at all like the selectively advertised in movies like Eternal Sunshine of the Spotless Mind or Paycheck, and there is no reason now to believe that type of selectivity can be achieved.

It is fascinating because it turns memory models on their heads. What is the mechanism of PKCzeta's maintenance of memories. We know that the AMPA receptors inserted into potentiated synapses are constantly treadmilling. Does it support this treadmilling and push it towards an equilibrium state with more inserted AMPA receptors?

By the way, I know that the initiated will recognize that this is not the first paper to show that PKCzeta has this effect. The difference between this recent paper and the older ones is that this one is the first to show this activity in cortical memory. Previous studies had only shown this effect in hippocampal LTP. The important to take away is that mechanism of memory appears to be similar whether we are talking hippocampus or cortex. This is something we largely already knew, but it is important to confirm these things.