Making mice forget

Manipulating the brain to over-express a protein can selectively erase short- and long-term fear memories in mice without compromising other memories or harming neurons, according to a study out this week in Neuron. The findings offer "a molecular paradigm by which we can actually erase a specific memory," linkurl:Joe Tsien,;http://www.gra.org/EminentScholarsDetail/tabid/368/xmmid/1072/xmid/193/xmview/2/school/Medical%20College%20of%20Georgia/Default.aspx a neuroscientist at the Medical College of Georgia and lead author of the paper, told The Scientist in an Email. "This opens a door to better understand memory circuits in the brain." When working with the neurotransmitter NMDA to create a transgenic "smart mouse" he called linkurl:Doogie;http://www.the-scientist.com/article/display/53346/ in the late 1990s, Tsien noticed that a downstream protein, Calmodulin-Dependent Protein Kinase II (CaMKII), physically interacted with the receptor for NMDA. To better understand CaMKII's involvement in the various stages of memory -- learning, consolidation, storage, and recall -- Tsien's group developed a linkurl:transgenic mouse;http://www.pnas.org/content/100/7/4287.abstract that over-expressed αCaMKII, a form of the protein. The researchers designed their knockout to allow them to closely control protein expression. Injecting a chemical inhibitor of the protein expressed by the transgene dampened αCamMKII expression, while a different injection flipped expression back on again. They then tested the ability of the engineered mice to remember objects and associate an environment with fear-inducing stimuli, which included an linkurl:electrical shock;http://www.the-scientist.com/article/display/14862/ to the paws and inescapable cat odor, after one hour. Mice over-expressing αCaMKII appeared unable to remember stimuli in comparison to the normal mice in short-term memory tests. The researchers could eliminate the mouse memory deficit by chemically suppressing αCaMKII expression. A month later, the effect still held: Whereas the month-old memories of foot-shock and cat odor caused normal mice to freeze with fear when placed in original testing environment, mice with overexpressed αCaMKII appeared comparatively blasé in the same environment. Many researchers believe CaMKII to be "the key molecule underlying learning and memory," linkurl:Mark Mayford,;http://www.scripps.edu/cb/highlights/mayford.html a neuroscientist at The Scripps Research Institute, who was not involved in the study, explained to The Scientist. Tsien's work not only reaffirms this belief, but provides "the most precise manipulation of [CaMKII]" researchers have been able to achieve to date, he said. The study may one day facilitate researcher's ability to erase memories using chemical manipulations for the treatment of linkurl:post-traumatic stress disorder;http://www.the-scientist.com/article/display/12699/ (PTSD), a disorder with limited treatment possibilities, Mayford said. "If we understood the molecular underpinnings of a desired pharmacological therapy, so that a patient could take drug, during memory recall," the treatment could proceed more rapidly. Still, Tsien cautions that his study is nowhere near reaching clinical application at this time. "One may start to look for the downstream substrates of the CAMKII over-expression as possible drug target(s)," he said. "Personally, I don't think it is possible in human[s]. However, [if] that happens in my life time, I wouldn't be surprised either."

Making mice forget

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