Mutant mice lead to memory insights

06/18/04



Two strains of mutant mice with crippled versions of a key memory molecule have led researchers to an understanding of both normal memory function and the memory problems that plague sufferers of an inherited disorder.

The researchers said their findings suggest that drugs already being tested for cancer and Huntington's disease might be useful in restoring some memory capability to patients with Rubinstein-Taybi syndrome (RTS). RTS is a heritable disorder characterized by mental and growth retardation and skeletal abnormalities. In humans, RTS occurs in about one in 125,000 births. The researchers propose that their findings could lead to treatments for RTS and other memory disorders as well as a means of improving memory in otherwise healthy individuals.

Two groups of researchers independently studied mutant mice deficient in "CREB binding protein" (CBP), which is a common target in patients with RTS. CBP is so named because it binds a key gene-regulating protein called CREB that is important for many functions including memory in animals from mollusks to humans.

CBP is a particularly hard-working protein. It serves as a molecular scaffold that helps assemble the machinery of gene transcription known to be necessary for formation of long-term memories. And critically, CBP acts as an enzyme that transfers acetyl groups onto the histone proteins that are part of the chromatin enfolding DNA in the chromosomes. Such acetylation is a central process in remodeling the chromatin to prepare the chromosome for gene transcription.

In one paper, Eric Kandel and his colleagues studied a mutant mouse -- developed in another laboratory -- in which one of the two copies of the gene for CBP had been knocked out. Such "haploinsufficiency" is thought to be a good animal model for Rubinstein-Taybi syndrome, because it mimics many of the symptoms of the disease.

In their studies, the researchers sought to understand whether such haploinsufficient mice showed the same kinds of memory defects as people with RTS. In particular, the scientists found that the mutant mice showed an impaired long-term memory. They were less able than normal mice to remember having encountered novel objects in their environment and less able to remember that a specific environment or tone would be associated with a mild but unpleasant shock.

Kandel and colleagues also found alterations in the brain circuitry of the mutant mice that suggested impairment of the machinery of long-term memory storage.

Importantly, they also found evidence that restoring the acetylation activity might alleviate such memory problems. In those experiments, they administered both to brain slices from the mutant mice and to the mice themselves a drug that inhibits de-acetylation -- thereby maintaining a higher level of acetylation of histones. They found that the circuitry of the brain slices returned to normal, and the mutant mice that received the drug showed a reversal of their memory deficits.

"Our study therefore suggests that it might be possible to use the same … inhibitors that are currently being tested in cancer and Huntington's disease as therapeutic compounds for RTS," wrote the researchers.

In the other paper, Edward Korzus and his colleagues created a sophisticated knockout mouse to pinpoint whether CBP's role in histone acetylation is central to its function in forming long-term memories. Their mutant mouse was constructed such that the researchers could switch on a "dominant-negative" form of the CBP gene -- which would eliminate normal gene function -- only in adult mice and only in the brain region known to be involved in memory formation. They could also switch this gene off, restoring normal CBP gene function. Importantly, the protein made by this dominant-negative CBP gene lacked only the ability to add acetyl groups to histone proteins -- called acetyltransferase activity -- but retained the ability to act as a molecular scaffold.

The researchers found that when they switched on the "bad" CBP gene, the mice showed impaired ability to form long-term memories of novel objects or the position of a submerged platform in a water tank. However, when they switched off the bad gene, the mice showed normal long-term memory formation.

In experiments similar to those of the Kandel group, Korzus and his colleagues also found that a drug that inhibits the removal of acetyl groups from histones restored long-term memory formation in the animals.

"The observation that acetyltransferase activity plays a critical role in memory consolidation may open new avenues for the investigation and treatment of memory disorders as well as provide new opportunities for memory improvement," wrote the researchers.

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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