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Forget It: Old Theory on Amnesia May Be Wrong

New study counteracts neurobiological dogma, which says inhibiting new protein formation in the brain causes memory loss
woman can't remember



© ISTOCKPHOTO/PAUL VASARHELYI
Forty years of neurobiological research states that short-term memories are formed by modifying proteins, whereas long-term memories are shaped by new proteins. Thus, a class of drugs known to inhibit brain cells from manufacturing proteins are also known to prevent new memory formation, resulting in a form of amnesia.

A new study in Proceedings of the National Academy of Sciences USA could turn this long-held notion on its ear, paving the way to new therapies for Alzheimer's and other diseases that cause dementia and memory loss. While researching the biochemical action triggered by the protein synthesis inhibitor anisomycin in the amygdala (involved in the formation of emotional memories), neuroscientists at the University of Illinois at Urbana-Champaign noted a strange occurrence in the midbrain region. The levels of three neurotransmitters—norepinephrine, dopamine and serotonin—shot up 1,000 to 17,000 percent higher than their normal levels before abating to well below normal for eight to 48 hours.

"We know that anisomycin causes the large release of neurotransmitters," says senior study author Paul Gold, a professor in the university's Brain and Cognition Division. "Those neurotransmitters themselves regulate memory formation and that's the basis of the particular phenomenon."

Gold and his colleagues began their research on lab rats believing that neurotransmitter fluctuation modulated memory formation. To test their hypothesis, they placed the animals in a cage with one well-lit and one darkened compartment. During the training phase of the experiment, each time a rat ventured into the dark side, they would receive a shock to their feet. Forty-eight hours later, their memory was assessed by their hesitation to enter that compartment.

The team then injected anisomycin and propranolol, a drug that blocks norepinephrine receptors in the brain, into the amygdalae of rats. "We [essentially] blocked the biological consequences of the release of norepinephrine," Gold says, noting that it minimized the rats' memory loss, evidenced by their reluctance to enter the shock-inducing dark chamber. The amnesia caused by anisomycin was also less pronounced when they injected the rats with clenbuterol, a drug that causes norepinephrine release, when their neurotransmitter levels were low. Finally, when a high dose of norepinephrine was administered in lieu of anisomycin, before training, the excess neurotransmitter levels caused amnesia (just as the protein synthesis inhibitor had).

"Together," the study says, "these findings suggest that intra-amygdala injections of anisomycin interfere with memory formation by inducing extraordinary changes in the release profiles of [norepinephrine, dopamine and serotonin]." Gold adds that follow-up studies will help determine whether all protein synthesis inhibitors have the same effect on neurotransmitters and, also, whether these findings apply to other brain regions.

Yadin Dudai, a neurobiologist at the Weizmann Institute of Science in Rehovot, Israel, notes that protein synthesis has been known to modulate neurotransmitter levels since the 1960s. He adds that the link between novel protein production and memory formation has been observed in several neural circuits in organisms ranging from mollusks to mammals. "I am not confident that the results of this interesting paper indeed demote a dogma," Dudai says. "However, I am supportive of any attempt to reverify the role of macromolecular synthesis observed immediately after the encoding of memory."

According to Gold, if the neurotransmitter fluctuation-based view does demote the dogma, there could be implications for researchers searching for drugs to counteract the effects of dementia that occur in diseases such as Alzheimer's. Researchers will have new targets—neurotransmitters rather than proteins—toward which to tailor their therapies.

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