Researchers Find Enzyme Crucial to Preservation of Memories

Description And Advantages

Using a technique to eliminate the function of one enzyme in a restricted memory-related region in the brains of mice, researchers have shown that the enzyme is important in consolidating long-term memories.

According to the researchers, their experiments - which showed that defects in a key biochemical signaling pathway were responsible for the animals' inability to improve their long-term memory in a series of maze tests - constitute a powerful approach to understanding molecules involved in learning and memory.

In an article published in the September 21, 2001, issue of Cell, Howard Hughes Medical Institute investigator Susumu Tonegawa and colleagues at the Massachusetts Institute of Technology and the Vollum Institute reported that elimination of the enzyme, calcium-calmodulin dependent kinase (CaMKIV), in the forebrains of mice had profound effects on signaling pathways in the brain and learning behavior.

The scientists began their studies to clarify the enzyme's role in late long-term potentiation (L-LTP), the process by which enduring memories are established through a mechanism of activating genes that trigger protein synthesis. This protein synthesis, in turn, alters the synapses- connections between neurons - and "etches" permanent memory pathways.

"CaMKIV had been implicated in long-term memory pathways in the past, but previous studies had involved global knockout of the enzyme in the entire animal," said Tonegawa. "Such knockouts gave inconsistent results because they affected the whole brain throughout development. We decided to use a technique to inhibit the protein only in the forebrain, which is more involved in higher brain function."

Tonegawa said that other research groups had attempted to knock out a protein called CREB, which is involved in turning on gene transcription in L-LTP, and which was believed to be activated by CaMKIV. The results of these studies were inconclusive, Tonegawa said, because there appeared to be multiple forms of CREB that could compensate for any knockout.

Tonegawa and his colleagues used a genetic technique that allowed them to replace the normal CaMKIV with a "dominant negative" mutant enzyme that would be produced only in the forebrains of the mice. Dominant negative enzymes have all of the characteristics of the functioning enzyme - such as an ability to bind normally to other molecules - but they lack the ability to carry out an appropriate enzymatic reaction.

Source

Chronicle Pharmabiz, September 27, 2001