June 20, 2005 Learning and memory are processes that link experience with behavior and therefore play central roles in our daily experience. That there exists a physical basis for these processes seems at first hard to imagine--except for the fact that physical disruptions in the brain, such as stroke or disease, can make them go wrong. This week, researchers report that by making targeted genetic disruptions that disable a key neurotransmitter receptor in the fruit fly, they have uncovered an important clue to the physiological mechanisms at work in learning and memory.
The subject of the study was the so-called NMDA receptor--a neurotransmitter receptor possessing special properties that could make it especially useful in learning and memory. In particular, past work has shown that NMDA receptors can respond in a special way to concurrent events on both sides of a synapse. Acting in this way as "coincidence detectors," NMDA receptors may help neurons form stronger or weaker connections with each other depending on whether they are repeatedly stimulated together. Neuroscientists strongly suspect that this process--called synaptic plasticity--of modulating the strength of synaptic connections on the basis of experience forms an elemental, neuron-level basis for learning and memory.
In the new work, the researchers sought to overcome technical hurdles that have stood in the way of understanding when and how NMDA receptors function in learning and memory. The research team, led by Tim Tully of Cold Spring Harbor Laboratory and Ann-Shyn Chiang of National Tsing Hua University, Taiwan, first used a genetic mutation to show that NMDA receptors are required for associative, or Pavlovian, learning in the fruit fly; they then went on to show that these receptors are not just passively participating but are in fact actively needed for both associative learning and long-term memory. The researchers demonstrated this active requirement by molecularly disrupting previously normal, functioning NMDA receptors in an adult fly and then showing that the fly had major difficulties in learning to associate an odor with a footshock--something that normal flies can quickly learn to do. The researchers found that flies with newly disrupted NMDA receptors could, with extended training, eventually learn to associate an odor with a footshock but that their long-term memory appeared to be completely abolished.
A main reason why these findings are significant is because past genetic work on the NMDA receptor relied on disrupting the receptor via genetic mutation, which could cause in the brain's wiring developmental defects that might undermine learning and memory in non-specific ways. The researchers' approach of disrupting the receptor at a specific time in an otherwise-normal adult brain ruled out such potentially confounding developmental effects.
The acute requirement for NMDA receptors strengthens the case that they play a central molecular role in synaptic plasticity--potentially by virtue of their ability to act as coincidence detectors that allow neuronal communication to extend beyond simple send-and-receive messaging. Because NMDA receptors are found in very distantly related animal species, they may represent an evolutionarily ancient component of synaptic function and synaptic plasticity.
The researchers include Shouzhen Xia, Lori Pyzocha, and Tim Tully of Cold Spring Harbor Laboratory; Tomoyuki Miyashita of Tokyo Metropolitan Institute for Neuroscience; Tsai-Feng Fu, Wei-Yong Lin, Chia-Lin Wu, and Inn-Ray Lin of National Tsing Hua University; Minoru Saitoe of Tokyo Metropolitan Institute for Neuroscience and Japan Science and Technology Agency; and Ann-Shyn Chiang of National Tsing Hua University and National Tsing Hua University.
The work was supported by the National Institutes of Health and Dart Neurosciences, Inc., by the Naito Foundation, Kato Memorial Bioscience Foundation, and grant-in-aid from the Ministry of Education, Sciences, and Sports Culture of Japan, and by the National Science Council, the Brain Research Center of the University System of Taiwan, and the Technology Development Program of Ministry of Economy, National Center for High-performance Computing, and Dart Neurosciences, Inc. T.T. is a paid consultant to Helicon Therapeutics, Inc. As a cofounder of Helicon, he owns less than 5% of the company.
Publishing in Current Biology, Volume 15, Number 7, pages 603-615. http://www.current-biology.com
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