Working with rodents, scientists have been able to selectively and safely remove both new and old memories by using a protein critical to brain cell communication. "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 (pictured), co-director of the Brain & Behavior Discovery Institute at the Medical College of Georgia School of Medicine. Reporting in the journal Neuron, Dr. Tsien explained how his investigations centered on an abundant protein found only in the brain called αCaMKII, which functions as a major signaling molecule for NMDA receptors (NMDA (N-methyl D-aspartate) receptors receive messages from other neurons). He found that when he over-expressed αCaMKII while a memory was being recalled, that single memory was eliminated.
Dr. Tsien says that NMDA receptors 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 (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) 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.
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, Dr. Tsien cautions that much more work needs to be done before the process could be applied to humans.
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Source: Medical College of Georgia
