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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.
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