March 09, 2001
Scientists Discover Memory-Enhancing Switch
Scientists have genetically engineered mice with enhanced memory
that persists until researchers switch it off by removing a drug that
controls a gene that encodes a key memory-governing enzyme. With
enhanced memory, the mice perform better on memory tests and then
revert to normal when the drug is removed.
The achievement, say the researchers who developed the mouse model,
offers important insights into the delicate molecular balance by which
memory storage is achieved. Although memory-boosting drugs are a long
way off, the researchers believe that the work opens new avenues for
understanding the molecular basis of memory.
“While it’s quite uncertain at this point, these findings could yield a useful target for drugs designed to enhance memory in people with age-related memory loss, although not for those with serious memory loss due to Alzheimer’s disease. Such drugs might prove to be the ‘aspirins’ of memory -- in the sense that they are able to enhance memory modestly.”
Eric R. Kandel
Howard Hughes Medical Institute (HHMI) investigator Eric R.
Kandel and his colleagues reported their experiments in the March
9, 2001, issue of Cell. Lead co-authors of the paper are
Gaël Malleret and Isabelle Mansuy, who was formerly in
Kandel’s Columbia University laboratory. Mansuy is now at the
Swiss Federal Institute of Technology in Zürich.
The scientists created the mice by inserting a gene that, when
activated by the antibiotic doxycycline, produces an inhibitor of the
enzyme calcineurin. In the brain’s principal memory-storage
region, the hippocampus, calcineurin counteracts the effects of another
enzyme, PKA, in signaling pathways governing a process called long-term
potentiation (LTP). LTP enhances connections between neurons and is one
of the main neural pathways by which memories are stored in the brain.
PKA is a kinase, which adds a phosphate to enzymes, and calcineurin is
a phosphatase, which removes a phosphate.
Development of the mouse was prompted by an earlier study conducted
at the HHMI laboratories at Columbia University with Cell
co-authors Danny G. Winder and Isabelle Mansuy, said Kandel. "In that
study, we overexpressed calcineurin in mice using this same system by
which genes can be switched on and off," said Kandel. "And, we saw that
such overexpression inhibited a component of LTP, and interfered with
memory storage. We reasoned that inhibiting the action of calcineurin
would enhance LTP and memory storage."
After developing the mice, the scientists first performed
biochemical studies on slices of hippocampus and electrophysiological
studies in whole mice that confirmed that doxycycline enhanced LTP. The
whole-animal studies were performed by co-authors Tim V. P. Bliss and
Matthew W. Jones of the National Institute for Medical Research in
London. "The whole-animal studies allowed recording the effects of
calcineurin inhibition for days and convinced us that we were really
seeing an enhancement of LTP even in the intact animal," said
Kandel.
The researchers next measured the animals’ memories in
behavioral tests. The researchers found that the calcineurin-inhibited
animals were better able to remember when familiar objects were moved
to novel locations or replaced with novel objects. The
calcineurin-inhibited mice were compared to both normal mice and mice
that had been taken off doxycycline.
"An important point is that we built into this experiment tests
showing that we could reverse the memory enhancement by switching off
the inhibitory gene," said Kandel. "You worry in such experiments that
the animals’ memory will become better or worse because
you’ve somehow interfered with some normal function during
development. But we found that was not the case; and we also did
experiments showing that the animals can see, smell and locomote
perfectly well, and are well motivated. So we really are seeing an
effect on hippocampal learning."
In other studies, the scientists showed that the
calcineurin-inhibited animals displayed enhanced spatial
memory—they were better able remember the location of a platform
in a murky water pool. And, the scientists performed tests showing that
working memory—memory of immediate past circumstances—was not
affected by the inhibition. In those tests, the animals were required
to find food in a radial-arm maze, a task enhanced by immediate recall
of the maze arms already explored.
According to Kandel, the mouse studies revealed the importance of a
balance of activation and inhibition in memory storage. "One tends to
think of memory storage as a process that is only positively directed,
involving a mechanism that allows you to store memories," he said. "But
our earlier work on lower organisms had revealed inhibitory constraints
on memory storage, and in this present work, we demonstrate the first
evidence for an inhibitory threshold in a mammalian brain. It confirms
what is really common sense—that you only want to store important
things in memory, so you need inhibitory constraints that you have to
overcome."
Kandel emphasized that further study will likely reveal other
balancing mechanisms. He also emphasized that practical applications in
the form of memory-enhancing drugs remain possible, yet unclear.
"While it’s quite uncertain at this point, these findings
could yield a useful target for drugs designed to enhance memory in
people with age-related memory loss, although not for those with
serious memory loss due to Alzheimer’s disease," he said. "Such
drugs might prove to be the ‘aspirins’ of memory—in
the sense that they are able to enhance memory modestly," he said.
Kandel cautioned that any memory-enhancing drugs that target
calcineurin would have to be quite specific since calcineurin plays a
number of important roles in the body, especially in the immune
system.
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