Hobbie and Doogie: Brainier Rodents With A Therapeutic Potential

C.S. Lewis’ novel The Magician’s Nephew tells of two children named Polly and Digory living in early 20th century London who set off on an adventure to explore a tunnel that runs through the roof of their row of terraced houses (1).  They eventually end up in a strange world ruled by Aslan—a talking lion whose goodness seems altogether repulsive to the evil forces that abound therein. With scenes of jackdaws and moles later competing to see who can be the first to tell a joke, we see in Lewis an author who knows how to inject humor into an otherwise serious message (1).

While recent collaborative studies by groups in China and the United States have not given us Lewis-style talking animals, they have provided some stunning insights into animal memory and learning behaviors.  Specifically Deheng Wang and colleagues from Shanghai, Yunnam and the Medical College of Georgia (MCG) generated a transgenic rat strain, affectionately known as ‘Hobbie-J’, that over-expressed a subunit of the brain NMDA (N-methyl D-aspartate) glutamate receptor called NR2B (2-3).  Their behavior experiments repeatedly showed Hobbie-J rats outperforming control litter mates in object recognition and spatial memory tests (2).

Pivotal to such an improvement in memory is a process known as Long Term Potentiation (LTP), which causes an enhancement of signal transmission between neurons in the hippocampus.  Selective antagonists against the NR2B subunit have confirmed its role in kick-starting LTP (2).  These findings come almost a decade after members of the same team hit the headlines with their announcement of a strain of ‘brainier’ mice, this time nicknamed ‘Doogie,’ that had been similarly modified to increase NR2B expression (4).    

The NR2B subunit plays a critical role in the brain’s ability to detect and remember simultaneous neural signals: feeling pain while seeing our fingers in the flame of a candle for example (4-5).  Extensive studies have shown that as we age, such signals must align more closely as they reach the brain if they are to create long lasting memories (4).  Importantly Doogie mice display longer age-dependent neuronal current decay times and prolonged opening of NMDA receptors than wild-type animals—an effect that lengthens the window of time over which simultaneous neural signals can be detected by the brain (5). 

Commenting on the age-related effects of NR2B levels, MCG neurologist Joe Tsien noted that “younger brains have higher amounts of this NR2B subunit, which leaves communication channels between brain cells open longer. That is why young people can learn faster than older adults” (6).  A fascinating reciprocal effect was observed with another signaling molecule called α-CAMKII (6).  Tsien’s group found that specific memories could be eliminated if α-CAMKII was expressed in mice at the precise moment that such memories were being recalled (6). 

In 1949 the late Canadian psychologist Donald Hebb proposed that “learning and memory are based on modifications of synaptic strength among neurons that are simultaneously active” (5).  A decade of ground-breaking research has today given credibility to Hebb’s 60-year old hypothesis and bestowed upon the medical profession a much-needed hope that we may someday have a gene therapy-based treatment against memory-destroying diseases, notably Alzheimer disease and other dementias (3-5).  As the pioneers of this work have been quick to point out “the identification of NR2B as a molecular switch in the memory process has indicated a potential new target for the treatment of learning and memory disorders” (5).

The unfolding story of NR2B’s therapeutic applications also finds a parallel in C.S Lewis’ much-celebrated epic.  For it is in returning to London with a special apple from the orchards of the mysterious world  that Digory is finally able to cure his terminally-ill mother (1). Indeed the attending doctor refers to her recovery as the ‘most extraordinary case’ he has seen in his entire medical career (1).  One can only live in hope that the exploits of medical research will produce similarly miraculous transformations in the mental ailments that affect our modern day.

Literature Cited

  1. Lewis, C.S. (1955) The Magician’s Nephew, Taken from The Chronicles Of Narnia, Harper Collins Children’s Books, New York, pp. 11-106
  2. Wang, D. et al (2009) Genetic Enhancement of Memory and Long-Term Potentiation but Not CA1 Long-Term Depression in NR2B Transgenic Rats, PLOS One 4, E7486
  3. Smart Rat ‘Hobbie-J’ Produced By Over-expressing A Gene That Helps Brain Cells Communicate. ScienceDaily
  4. Leutwyler, K. (1999) Making Smart Mice Scientific American 7 Sept. 1999.
  5. Tang, Y-P. et al (1999) Genetic enhancement of learning and memory in mice. Nature, Volume 401, pp. 63—69
  6. Baker, T. (2008) Memories Selectively, Safely Erased In Mice. Medical College Of Georgia News, 22 Oct. 2008.
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Robert Deyes

Robert Deyes

Robert has been a Technical Services Scientist at Promega for over 10 years. He also worked for two years as a Technical Advisor at the Paisley, Scotland facility of Life Technologies Inc. After earning his Masters in Medical Genetics from the University of Glasgow, he spent 18 months at the Université Louis Pasteur in Strasbourg, France where he did research into the molecular basis of the inherited disorder Spinal Muscular Atrophy. He also holds a BSc from the University of Portsmouth in England.
Robert Deyes

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