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Volume 90 Issue 8 | p. 11 | News of The Week
Issue Date: February 20, 2012

Memories’ Sweet Origins

Neurochemistry: Sugar-protein interaction helps control memory
Department: Science & Technology
Keywords: O-GlcNAc, carbohydrates, gene expression, memory, brain chemistry, neurons, axons, dendrites
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Axon and dendrite growth in mice is reduced by O-GlcNAc-modified CREB (left) and promoted by nonglycosylated CREB.
Credit: Courtesy of Linda Hsieh-Wilson
O-GlcNAc-modified CREB (left) deters axonal growth (shown), gene expression, and memory formation, whereas nonglycosylated CREB (right) promotes them.
 
Axon and dendrite growth in mice is reduced by O-GlcNAc-modified CREB (left) and promoted by nonglycosylated CREB.
Credit: Courtesy of Linda Hsieh-Wilson
Mice expressing O-GlcNAc-glycosylated CREB or non-glycosylated CREB were trained to associate a tone with a brief unpleasant stimulus. After 2 hours, they were tested for whether they had remembered to associate the tone with a fear behavior, in which they stop all activity or “freeze.” Shown here are mice with glycosylated CREB, which show less freezing behavior than mice with non-glycosylated CREB, suggesting that glycosylation impedes long-term memory formation.
Credit: Video by Jessica Rexach, copyright 2012 by Linda Hsieh-Wilson and coworkers, Caltech
Mice expressing O-GlcNAc-glycosylated CREB or non-glycosylated CREB were trained to associate a tone with a brief unpleasant stimulus. After 2 hours, they were tested for whether they had remembered to associate the tone with a fear behavior, in which they stop all activity or “freeze.” In this video, mice with non-glycosylated CREB showed increased freezing behavior, as compared to mice with glycosylated CREB. This enhancement of memory after 2 hours indicates that long-term memory formation is accelerated in mice with non-glycosylated CREB.
Credit: Video by Jessica Rexach, copyright 2012 by Linda Hsieh-Wilson and coworkers, Caltech

Little did entertainer Bob Hope know that “thanks for the memory” not only is a moving song lyric but also acknowledges the effect of making changes in sugar molecules on a brain protein.

Researchers have found that O-linked β-N-acetyl-d-glucosamine (O-GlcNAc) discourages memory formation when it’s attached to the transcription factor CREB and that memory improves when the sugar is removed or absent (Nat. Chem. Biol., DOI: 10.1038/nchembio.770). The finding reveals a previously unknown sugar-based mechanism for regulating gene expression, neural development, and memory. It could lead to new ways to enhance memory or to reduce memory loss among patients with diseases such as Alzheimer’s.

O-GlcNAc modification of proteins was known to influence brain development, neuronal signaling, and neurodegeneration. But how it affects such processes on a molecular level had been uncertain.

Using a sugar-tagging technique they developed, carbohydrate chemist Linda C. Hsieh-Wilson of California Institute of Technology and coworkers have shown for the first time the profound effects of O-GlcNAc on the transcription factor CREB. Working with mice, they found that gene expression, neuronal axon and dendrite growth, and memory formation are reduced by CREB glycosylation with O-GlcNAc and promoted by blocking that glycosylation.

The same three processes are enhanced by CREB phosphorylation and reduced by CREB dephosphorylation. Phosphate and O-GlcNAc appear to work together, albeit in an opposite way.

Together with many prior studies, the work shows “how the fields of neurobiology, transcription, and signaling need to pay attention to this ubiquitous sugar modification of proteins to understand biology at the molecular level,” says O-GlcNAc expert Gerald W. Hart of Johns Hopkins University. “Focusing only on phosphorylation will reveal only part of the story.”

How memories are made “is one of the great biological mysteries,” says another O-GlcNAc specialist, John A. Hanover of NIH. The new findings “provide an important clue” to better understand that process.

 
Chemical & Engineering News
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