Genetically Modified “Smart” Mice Remain Smart into Old Age

Contact: Gina M. Digravio, 617-638-8491 | gina.digravio@bmc.org

(Boston) – Boston University School of Medicine (BUSM) researchers report that genetically modified “smart” mice, created by boosting the production of NR2B protein in the brain, have maintained their superior learning and memory function even at advanced age. The findings, which currently appear online in the European Journal of Neuroscience, point to a potential target for improving learning and memory in the aging brain.

The current studies are the most recent in a long series of investigations focused on understanding which genes and proteins play key roles in regulating the way nerve cells communicate with each other – and how they lay down memories in the brain. This research has been led by neurobiologist Joe Z. Tsien, PhD, director of the Center for Systems Neurobiology in the Department of Pharmacology & Experimental Therapeutics at BUSM, and a joint professor in the Department of Biomedical Engineering at Boston University.

This group of researchers had previously discovered that the gene, called NR2B, is a key switch that controls the brain’s ability to associate one event with another, the core feature of learning and memory. In 1999 while working at Princeton University, Tsien noticed that juvenile brains seem to have more NR2B protein than the adult brain does, and showed that the increased production of the NR2B in the forebrain regions led to superior learning and memory in adult mice.

In the current work, the investigators set to measure the long-term effect of the over-expression of the NR2B gene on overall well-being of learning and memory function during the aging process. “Since the endogenous NR2B level is known to be down-regulated before the onset of sexual maturity across many animal species, some researchers have speculated whether this evolutionarily conserved NR2B down-regulation in the adult brain might reflect a protection mechanism for reducing the risk of neurotoxicity caused by possible ‘high calcium influx’ through the NR2B-containing NMDA receptor, thereby preventing drastic declines in cognition during the adulthood,” said Tsien. “Based on this argument,” he added, “one would predict that long-term NR2B over-expression in the brain may revert from the initial enhancement of learning and memory in young adulthood to severe cognitive impairment at older ages.”

“Instead, we found these old transgenic mice still exhibited superior learning and memory function even at an advanced age as assessed by five different memory tests,” said Xiaohua Cao, the first author of the paper, and a former postdoctoral associate in Tsien’s lab. Cao is currently a faculty member at The Shanghai Institute of Brain Functional Genomics of East China Normal University in China, “This strongly indicates that the evolution exerts its pressure on survival up to a point of reproduction, not for living forever.”

“These studies address the question of whether long-term over-expression of the NR2B is beneficial for, or detrimental to, learning and memory function,” said Zhenzhong Cui, another postdoctoral associate in Tsien’s lab and second author of the paper. “Our current study clearly shows that the persistent up-regulation of the NR2B subunit is beneficial for improving learning and memory function in the aged brain.”

According to the researchers, taken together, these results could be of major interest to researchers trying to understand and treat human disorders that involve the loss of learning and memory during aging. In particular, the NR2B gene could be a valuable target for drug makers, who could try to design medicines that boost its effects. At this point, it has been shown that the corresponding gene exists in humans, but its enhancing effect in primates is not known.

This research was funded by National Institute of Mental Health and National Institute of Aging of NIH.