COVER STORY
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MEMORABLE MICE
McGill University's Mauro CostaMattioli holds mice that he genetically enhanced to have much better memories than regular mice.
HOLD THAT THOUGHT Slowly but surely, scientists are unveiling the complex CHEMICAL UNDERPINNINGS of memory SOPHIE L. ROVNER, C&EN WASHINGTON
WHEN WAS THE LAST TIME you misplaced your car in a parking lot? Gave you a bit of a scare, didn't it? What about when you blanked on the name of a longtime friend—did you wonder if you were showing the first signs of Alzheimer's disease? These are not trivial fears. Memory is as vital to your trip to the grocery store as it is to your role at work and to your very personality. To support these diverse responsibilities, memory is necessarily complex, and it has taken scientists more than a century to establish a basic understanding of its elaborate biochemical bases. Using isolated brain cells, brain scans, behavioral studies, pharmaceutical treatments, genetic engineering, and other tools, they have shown that memory is based on a series of biochemical events that induce changes in proteins in a network of the brain's MORE ONLINE
neurons and that a lasting memory also requires structural changes in those neurons. Researchers have discovered multiple genetic and pharmacological techniques to improve memory, an accomplishment that will no doubt capture the attention of an aging population (see page 22). They have also determined what happens when memory malfunctions. These findings could one day enable physicians to cure learning disabilities or to erase the unbearable memories associated with posttraumatic stress disorder. But there's still plenty more to find out. The process of forgetting isn't well-understood, for instance. Nor do scientists have a firm grasp on how long-term memories can persist despite the rapid recycling of many of the molecules involved in their storage. It's no wonder that the mechanism of memory is still something of a mystery.
"The brain is the most complex machine in the whole world, and maybe the universe," says Nahum Sonenberg, a biochemist at McGill University, in Montreal. It would be hard to dispute his assessment, given the mind-boggling statistics needed to describe this marvelous machine. The brain contains 100 billion neurons, each connected to thousands of other neurons via trillions of synapses. "It's a very comforting thought that your brain has at least an order of magnitude more synapses than there are dollars in the U.S. debt," muses Gary S. Lynch, a professor of psychiatry and human behavior at the University of California, Irvine. "That's a huge number of connections," adds Sonenberg. "And each time you see something, each time you learn something, you activate a different set of neurons" to form a unique memory of the event.
Visit www.cen-online.org to learn about the memory malfunctions that underlie posttraumatic stress disorder, the role of sleep in memory formation, and how the memory of a mouse was improved. WWW.CEN-0NLINE.ORG
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But how exactly is an event Axon terminal translated into a memory? Direction of nerve impulse Memory is constructed in stages. When the brain initially takes in an experience or a fact—such as a scene in a mov ie or an unfamiliar telephone number—the information first goes into short-term memory. By definition, a short-term memory is transient, and the information it contains can be N E U R O N A L S T I M U L A T I O N A nerve impulse forgotten after a few hours or travels from an axon terminal of one neuron even just a few seconds. But if across a synapse to a dendrite of another the information is freighted neuron. with sufficient weight—partic ularly if a person is paying close attention or if the information is associated versity. "The notion is that saliency—how with a stressful or emotional experience—it important that information is to you—can can be transferred into long-term memory, distinguish whether that information is where it can endure for as long as a lifetime. ultimately retained or not." "If there's some event—a gunshot goes Different types of information are direct off or some wonderful event happens—the ed to different regions of the brain's cortex, events surrounding that experience be the outer layer of the brain. Light given off come crystalline in your memory, even if by scenery in a movie, for instance, passes they precede that event," says Paul F. Worthrough the viewer's pupil and strikes rod ley, a neuroscientist at Johns Hopkins Uniand cone cells in the retina at the back of the eye. Pigment proteins in these cells absorb the light and convert its energy into a nerve ORGANIC SPECIALITIES impulse. Propagated by neurotransmit ters and ion flows in and out of nerves, that Trimethylsilylcyanide impulse then shuttles along the optic nerve CH3 to the thalamus and then into the visual cortex at the back of the brain. Music from CH 3 - Si - C N the sound track, on the other hand, passes from the ear through the thalamus and ends up in the auditory cortex in the middle of the outer sides of the brain. (Cyanotrimethylsilane)
TRIMETHYLSILYLCYANIDE (TMSCN) is useful achieving many chemical transformations in high yield and under mild reaction conditions. Nitrites are prepared from alcohols and TMSCN. Useful in the formation of an isonitrile. Schiffs bases are cyanosilylated to yield high purity optically active alpha-amino acids. ο sive," says Gary S. Lynch, a pro- 5 fessor of psychiatry and human 5 behavior at the University of | California, Irvine. if An effective memory aid > could get a warm welcome in £ our aging society, yet drug deg velopment has been slow. Only a few modestly effective drugs for treating memory problems associated with Alzheimer's disease are available, including acetylcholinesterase inhibitors and Namenda (memantine), which blocks the N-methyl-Daspartate (NMDA) receptor on neurons. But "by and large, this is an untapped area," says UCLA neurobiologist Alcino J. Silva. Many companies recognized the growth potential of the market and launched programs to develop cognition enhancers. Despite early enthusiasm for such products, however, the field "ran into molasses," because of the difficulties in pushing the drugs through the regulatory process, Lynch says. The main impediment has been convincing the Food & Drug Administration that it's acceptable to market this type of cognition-focused drug. Tim Tully, a neuroscience professor at Cold Spring Harbor Laboratory, in New York, who cofounded the drug company Helicon Therapeutics, thinks there's a plausible way ahead for memory-enhancing compounds. If Helicon can show that one of its compounds helps Alzheimer's patients, Tully believes, FDA might then allow the company to evaluate the compound for a less severe condition called mild cognitive impairment. Ultimately, he hopes, the compound could be tested for age-associated memory impairment, "which is essentially what a large fraction of all 50-year-olds suffer from. WWW.CEN-0NLINE.ORG
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MEMORY BOOSTER "Any people who Lynch stands are 50 or 55 and in before a sketch of the workplace would AM PA receptors, happily take a drug the targets of his firm's ampakine that could help imdrugs. prove their memory, because it would keep them competitive with the 30-year-old bucks who are vying for their jobs," Tully adds. "But age-related memory impairment is not really accepted as a medical need by FDA." Lynch agrees that "the government is not in the business of saying you can go out and sell drugs to treat what is a normal condition." But what about Viagra? Lost libido and the other symptoms the drug is intended to overcome "are perfectly normal conditions of aging," he points out. In the end, Lynch notes, "that says the government will probably recognize that it's okay to treat some of the other normal aspects of aging if we don't use the word 'disease.' " If a drug is approved for older people,
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however, it's likely to end up in the hands of younger people, and not al ways for its intended purpose, Lynch acknowledges. "The Ritalin experience has sensitized the world to the pos sibility of off-label or recreational use" of drugs. Ritalin (methylphenidate) is prescribed for its calming and focusing effect in patients with attention deficit hyperactivity disorder, but it's also a stimulant. "If youVe got to finish your term paper tonight," Lynch says, "stim ulants are going to help you do that." Drugs that improve memory also conjure up a problematic divide be tween the haves and the have-nots. If "you have access to this drug and some body else doesn't, and you're studying for an exam, you have an advantage over every one else," Lynch says. As society works through the ethics involved in enhancement, several academ ics and industrial researchers continue the hunt for compounds that can improve memory. UC Irvine's Lynch cofounded Cortex Pharmaceuticals to develop ampakines, which ease the process by which a
VOHo Η 3 ^ Ν Λ ^ Χ OH Η
AMPA
NMDA
GLUTAMATE COUSINS L-Glutamate is a neurotransmitter that acti vates receptors in the brain. There are four major classes of glutamate receptor, each of which plays a role in memory function. They include the NMDA and AMPA receptors, named after glutamate-like compounds (shown) that can also activate these glutamate receptors.
long-term memory is created, also known as long-term potentiation. These com pounds do so by enhancing the effects of glutamate on a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptors on neurons (see page 13). The first generation of ampakines spurs AMPA receptors to effect greater depo larization of neurons. That augmentation increases activation of the NMDA receptors
that trigger long-term potentiation. Second-generation ampakines that are under development additionally pro long the opening of AMPA receptors, resulting in even greater NMDA acti vation. These newer compounds also boost production of brain-derived neu rotrophic factor (BDNF). This growth factor is believed to increase production of new AMPA receptors and promote the growth and survival of neurons. The compounds, several of which are benzamides, have been shown to improve memory in humans. Cortex is currently conducting a clinical trial of one of the first-generation ampakines in Alzheimer's patients, Lynch says. Companies such as Memory Pharma ceuticals and Helicon are pursuing drugs that reduce the effort needed to form a long-term memory by enhancing activity of cAMP response element-binding protein (CREB), a transcription factor that's criti cal for memory consolidation. Memory consolidation is the process by which re cent memories are stored for the long haul. Examples of these drugs include inhibitors
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