Seniors Worry About Losing Memory but New Discovery
May Lead to Erasing Just the Bad Stuff
Dr. Joe Z. Tsien, brain scientist and co-director
of the Brain & Behavior Discovery Institute at the Medical
College of Georgia School of Medicine.
New and old memories have been selectively and safely
removed from mice
Oct. 22, 2008 Senior citizens usually worry about
losing memory but, for some, there may be a memory they wish would go
away. There may be a safe and easy answer on the way, say scientist who
have selectively and safely removed memories from mice.
"While memories are great teachers and obviously
crucial for survival and adaptation, selectively removing incapacitating
memories, such as traumatic war memories or an unwanted fear, could help
many people live better lives," says Dr. Joe Z. Tsien, brain scientist
and co-director of the Brain & Behavior Discovery Institute at the
Medical College of Georgia School of Medicine.
"Our work reveals a molecular mechanism of how that
can be done quickly and without doing damage to brain cells," says the
Georgia Research Alliance Eminent Scholar in Cognitive and Systems
Neurobiology.
Dr. Tsien's research team, in collaboration with
scientists at East China Normal University in Shanghai, were able to
eliminate new and old memories alike by over-expressing a protein
critical to brain cell communication just as the memory was recalled,
according to research featured on the cover of the Oct. 23 issue of
Neuron.
Dr. Tsien had already created a mouse that couldn't
form memories by eliminating the NMDA receptor, which receives messages
from other neurons. He then garnered international acclaim by making "Doogie,"
a smart mouse in which a subunit of the NMDA receptor is over-expressed.
Younger brains have higher amounts of this NR2B
subunit which leaves communication channels between brain cells open
longer. That is why young people can learn faster than older adults.
This time he was examining downstream cascades of
the NMDA receptor to learn more about memory formation. An abundant
protein found only in the brain, called αCaMKII, was a logical place to
look because it's a major signaling molecule for the NMDA receptor. He
found that when he over-expressed αCaMKII while a memory was being
recalled, that single memory was eliminated.
Receptors such as the NMDA receptor are like front
doors to cells, providing an opening for signaling molecules such as
calcium. Synapses are the point of communication between two cells, and
NMDA receptors are on the receiving end of the message. Like people,
neurons change with the signals they receive.
"Learning changes the way cells connect to each
other," says Dr. Tsien.
To form a memory, the NMDA receptor is activated,
which results in the insertion of AMPA receptors into those synapses and
subsequent strengthening of the synaptic connections among hundreds of
thousands of neurons. Scientists believe that αCaMKII plays an important
role in the insertion of AMPA receptors into synapses during learning
and subsequent strengthening of connections between neurons to create a
memory.
Memory has four distinct stages: learning,
consolidation, storage and recall. It has been difficult to dissect the
molecular mechanisms of these stages because researchers lacked
techniques to manipulate proteins quickly.
For example, when researchers disable a gene
suspected to play a role in the memory process, the deletion typically
occurred throughout the entire period so it was impossible to tell which
parts of processes were impaired. Previous technology would take several
days to switch off a protein, which is the product of a gene.
So Dr. Tsien's team developed a powerful
chemical-genetic method that allows him to use a pharmacologic inhibitor
to instantly turn αCaMKII off and on in a mouse that he genetically
engineered to over express this signaling molecule. That enabled him to
study exactly what happened if he threw off the natural balance during
the retrieval stage.
Much as a war veteran remembers a fateful patrol
when he was fired upon, mice can establish a very long-lasting emotional
memory about a place if, for example, they receive a mild shock to the
paws while there. The researchers showed if they over-expressed αCaMKII,
this powerful memory was rapidly erased as the animals tried to retrieve
them while other memories remained intact.
A similar approach was taken with object
recognition memory, giving mice a couple of toys to play with then
erasing their memory of one of them. "You will feel like every time,
it's a new toy," says Dr. Tsien.
While the ability to rapidly erase a selective
memory is exciting, he cautions that its translation to humans would be
difficult at this stage. "We are barely at the foot of a huge mountain,"
says Dr. Tsien. A possible strategy for humans would be a drug that
mimics the αCaMKII over expression that researchers accomplished through
genetic manipulation. Or, further downstream substrates that αCaMKII
acts upon could become possible drug targets.
Editors Notes
The research was funded by the National Institute
of Mental Health, the National Institute on Aging and the Georgia
Research Alliance.
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