Over-expressing a gene that lets brain cells communicate just a fraction of a second longer makes a smarter rat, report researchers from the Medical College of Georgia and East China Normal University.

Dubbed Hobbie-J after a smart rat that stars in a Chinese cartoon book, the transgenic rat was able to remember novel objects, such as a toy she played with, three times longer than the average Long Evans female rat, which is considered the smartest rat strain. Hobbie-J was much better at more complex tasks as well, such as remembering which path she last traveled to find a chocolate treat.

The report comes about a decade after the scientists first reported in the journal Nature that they had developed “Doogie,” a smart mouse that over-expresses the NR2B gene in the hippocampus, a learning and memory center affected in diseases such as Alzheimer’s. Memory improvements they found in the new genetically modified Long Evans rat were very similar to Doogie’s. Subsequent testing has shown that Doogie maintained superior memory as he aged.

“This adds to the notion that NR2B is a universal switch for memory formation,” says Dr. Joe Z. Tsien, co-director of the MCG Brain & Behavior Discovery Institute and co-corresponding author on the paper published Oct. 19 in PLoS One. Dr. Xiaohua Cao at East China Normal University also is a co-corresponding author.

The finding also further validates NR2B as a drug target for improving memory in healthy individuals as well as those struggling with Alzheimer’s or mild dementia, the scientists says.

NR2B is a subunit of NMBA receptors, which are like small pores on brain cells that let in electrically-charged ions that increase the activity and communication of neurons. Dr. Tsien refers to NR2B as the “juvenile” form of the receptor because its levels decline after puberty and the adult counterpart, NR2A, becomes more prevalent.

While the juvenile form keeps communication between brain cells open maybe just a hundred milliseconds longer, that’s enough to significantly enhance learning and memory and why young people tend to do both better, says Dr. Tsien, the Georgia Research Alliance Eminent Scholar in Cognitive and Systems Neurobiology. This trap door configuration that determines not just how much but how fast information flows is unique to NMBA receptors.

Scientists found that Hobbie-J consistently outperformed the normal Long Evans rat even in more complex situations that require association, such as working their way through a water maze after most of the designated directional cues and the landing point were removed. “It’s like taking Michael Jordan and making him a super Michael Jordan,” Deheng Wang, MCG graduate student and the paper’s first author, says of the large black and white rats already recognized for their superior intellect.

But even a super rat has its limits. For example with one test, the rats had to learn to alternate between right and left paths to get a chocolate reward. Both did well when they only had to wait a minute to repeat the task, after three minutes only Hobbie-J could remember and after five minutes, they both forgot. “We can never turn it into a mathematician. They are rats, after all,” Dr. Tsien says, noting that when it comes to truly complex thinking and memory, the size of the brain really does matter.

That’s one of the reasons scientists pursue this type of research: to see if increased production of NR2B in more complex creatures, such as dogs and perhaps eventually humans, gets the same results. He also is beginning studies to explore whether magnesium – a mineral found in nuts, legumes and green vegetables such as spinach – can more naturally replicate the results researchers have obtained through genetic manipulation. Magnesium ion blocks entry to the NMDA receptor so more magnesium forces the brain cell to increase expression levels of the more efficient NR2B to compensate. This is similar to how statin drugs help reduce cholesterol levels in the blood by inhibiting its synthesis in the liver.

Scientists created Hobbie-J and Doogie by making them over-express CaMKII, an abundant protein that works as a promoter and signaling molecule for the NMDA receptor, something that likely could not be replicated in humans. In October 2008, they reported in Neuron that they could also safely and selectively erase old and new memories alike in mice by over-expressing CaMKII while the memory was being recalled

“We want to make sure this is a real phenomenon,” Dr. Tsien says of the apparent connection between higher levels of NR2B and better memory. “You should never assume that discovery you made in a cell line or a mouse can be translated to other species or systems unless you do the experiments.” He adds that the failure of new drugs and other disappointments result from the lack of sufficient scientific evidence.

The transgenic rat has other practical value as well. There is substantial scientific and behavior data already available on rats and because rats are larger, it’s easier to do memory tests and record signals from their brain. For example they are strong enough to press levers to get a food reward and their size and comfort level with water means they won’t just float aimlessly in a water maze as “fluffy” mice tend to do.

Scientists prevented age-related changes in the hearts of mice and preserved heart function by suppressing a form of the PI3K gene, in a study reported in Circulation: Journal of the American Heart Association.

“The study provides evidence that delaying or preventing heart failure in humans may be possible,” said Tetsuo Shioi, M.D., Ph.D., senior author of the study and assistant professor of medicine at Kyoto University Graduate School of Medicine in Kyoto, Japan.

“Advanced age is a major risk factor for heart failure. One reason is that aging increases the chance of exposure to cardiovascular risk factors. However, natural changes due to aging may also compromise the cardiovascular system.”

According to the American Heart Association, 5.7 million Americans have heart failure, and nearly 10 out of every 1,000 people over age 65 suffer heart failure every year.

Shioi and his colleagues studied elderly mice genetically engineered to suppress the activity of one form of the PI3K gene, which is a part of the insulin/IGF-1signaling system that helps regulate the lifespan of cells.

A variation of PI3K, known as the p110? isoform, plays an important role in tissue aging. Suppressing the isoform’s activity in the roundworm C. elegans extends its life. And in fruit flies, suppression prevents the age-dependent decline of heart function.

The Japanese researchers compared aged mice with a functional p110? to aged mice with suppressed p110? and found that mice with the suppressed gene had:

• improved cardiac function;
• less fibrosis (fibrosis causes the heart to lose flexibility);
• fewer biological markers of aging; and
• a pattern of cardiac gene expression like that of younger mice.

“This study showed that aging of the heart can be prevented by modifying the function of insulin and paves the way to preventing age-associated susceptibility to heart failure,” Shioi said.

The researchers concluded that PI3K’s role in cardiac aging involved regulating other points further downstream in the insulin/IGF-1signaling pathway, which resulted in changes in how insulin acted in heart cells. The biological mechanism by which suppressing the gene’s activity improved the survival of the mice remains unclear.

“The heart failure epidemic in the United States and many other countries is due, in part, to our aging population,” said Mariell Jessup, M.D., an American Heart Association spokesperson and professor of medicine at the University of Pennsylvania School of Medicine in Philadelphia. “Aging humans experience a slow but gradual loss of heart cells and a host of other cellular and sub-cellular abnormalities which make the remaining cells contract less efficiently. Thus, this early work in a mouse model, clarifying the role of PI3K in cardiac aging, could ultimately allow scientists to understand if human hearts are similarly influenced.”

Co-authors are: Yasutaka Inuzuka, M.D.; Junji Okuda, M.D.; Tsuneaki Kawashima, M.D.; Takao Kato, M.D.; Shinichiro Niizuma, M.D.; Yodo Tamaki, M.D.; Yoshitaka Iwanaga, M.D., Ph.D.; Yuki Yoshida, M.D., Ph.D.; Rie Kosugi, M.D., Ph.D.; Kayo Watanabe-Maeda, M.D., Ph.D.; Yoji Machida, M.D., Ph.D.; Shingo Tsuji, Ph.D.; Hiroyuki Aburatani, M.D., Ph.D.; Tohru Izumi, M.D., Ph.D.; and Toru Kita, M.D., Ph.D.