NMDA receptor overexpression enhances memory and learning in mice

Reuters News

Transgenic mice created to overexpress the NMDA (N-methyl-D-aspartate) receptor 2B (NR2B) outperform their littermates in tests of memory and learning ability, according to a report published in the September 2nd issue of Nature.

"Our results suggest that genetic enhancement of mental and cognitive attributes such as intelligence and memory in mammals is feasible," Dr. Joe Z. Tsien, from Princeton University in Princeton, New Jersey, and colleagues write.

Normally, NR2B expression diminishes as animals age, the researchers explain. "This could decrease NMDA-mediated plasticity, and perhaps explain decreased memory performance in adult animals including songbirds, monkeys, and humans."

Dr. Tsien's team examined transgenic mice in which NR2B expression in the cortex and hippocampus was twice that of wild-type mice. According to the findings, NR2B overexpression in transgenic mice resulted in "...prolonged opening of the NMDA receptors...and enhanced NMDA activation in individual synapses, thus retaining several features of juvenile NMDA-receptor properties."

In turn, the authors write, transgenic mice showed selective enhancement of long-term synaptic potentiation (LTP), a phenomenon believed to be important in learning and memory, evoked by stimulation at 10 to 100 Hz. "As forebrain neurons often fire in this frequency range during behavioral experience," they propose, "...it is possible that the selective enhancement of potentiation by stimuli at [10 Hz or greater] in the transgenic mice is particularly meaningful."

Indeed, the performance of the transgenic mice in a novel-object-recognition task confirmed that these animals have better long-term memory than wild-type mice, even though both groups showed similar levels of curiosity and motivation during the task.

In tests of contextual and cued conditioning, the investigators report, transgenic mice learned more quickly than their wild-type littermates. Furthermore, "...spatial learning in transgenic mice was faster than in wild-type mice."

"Our results show that NR2B expression is critical for learning, memory, and higher cortical functions," Dr. Tsien said in an interview with Reuters Health. "And since the receptor and channel properties are nearly identical in mice and humans, I believe that human learning and memory share the same fundamental mechanism."

"This means we might be able to treat learning or memory disorders by targeting the brain with compounds that either mimic NR2B expression or somehow boost NR2B expression," Dr. Tsien added.

In the journal, the authors note that the study "...reveals a promising strategy for the creation of other genetically modified mammals with enhanced intelligence and memory."

"[This] work is striking for two reasons," Dr. T. V. P. Bliss, from the National Institute for Medical Research in London, UK, writes in a related commentary. "First, there is a clear link between manipulation of a specific gene (overexpression of the NR2B subunit) and the physiological consequence (enhanced Ca2+ flux, leading to greater LTP). The second reason is the variety of tasks examined, which adds strength to the authors' conclusion that they have indeed made a smarter animal."

Nature 1999;401:63-69,25-27.