By David N. Leff

Kids who visit Disney World are entranced by larger-than-life Mickey Mouse simulacra, which are the theme park¿s hallmark and icon.

On the campus at Princeton University in New Jersey, neurobiologist Joe Tsien has constructed what he calls ¿a Disney World for real, live, smart ¿ and dumb ¿ mice.¿ Here he measures the rodents¿ mental acumen at the brain-cell level, using learning and memory as gauges of their cognitive capacity. (See BioWorld Today, Sept. 2, 1999, p. 1.)

Learning and memory are largely the work of a small, complex, convoluted brain region called the hippocampus. A key neurotransmitter, the NMDA receptor (NMDAR) manages the neurons that produce learning, remembering ¿ and forgetting. ¿A major subregion in the hippocampus,¿ Tsien pointed out, ¿is called CA1. It¿s a trisynaptic pathway that acts as a relay station in processing local brain messages.¿

He and his colleagues have created a colony of fine-tuned knockout mice in which NMDAR is deleted. To amputate this crucial cluster of neurons, they employ ¿DNA scissors called Cre-Lox.¿ (Cre is an enzyme that recombines the memory genes containing certain sites called Lox.)

¿Our most recent goal,¿ Tsien told BioWorld Today, ¿was to examine the role of NMDA receptor activity in the formation of nonspatial memory, and the effects on it of enriched experience.¿ That is, the consequences of lacking savvy receptor neurons stacked up against nerve cells altered for the better by exposure to the full life in Tsien¿s Disney World.

That murine theme park, he narrated, ¿featured an enriched environmental training course, in which we randomly distributed knockout (KO) and wild-type adult littermates into two groups. One cohort, the naoves, lived in standard, bare-bones cages. The other group trained in an enriched environment three hours a day for two months. That training took place in specially designed boxes (1.5 meters by 80 cms, and 80 cms high) in which we surrounded them with various playthings. We made small cardboard castles, put in running wheels and Lego blocks ¿ objects we got at the toy store.¿

Fun Surroundings Trumped Loss Of Brain Marbles

¿The animals just explored,¿ Tsien recounted. ¿It was fun for them to walk around, in comparison to their naove littermates, confined to small cages where there was nothing to use or play with. The enriched ones walked around, sniffed around, explored everything, found food pellets. We kept rearranging the enrichment group¿s playthings, putting in different cardboard houses and new toys every few days to further stimulate their exploration.¿

Tsien reports the findings from this latest series of behavioral, genetic and anatomic experiments in the March issue of Nature Neuroscience. Its title: ¿Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice.¿

¿Those results showed two things,¿ he summed up: ¿The first is that normal mice did better than KO ones. And amazingly, most of those amnesic KO mice ¿ which usually had difficulty finding their way through a simple maze ¿ could reach that enriched level also. The second thing is that our KO mice performed comparably to the enriched mice. So it¿s not just reaching the level of the wild-type animals. Contrary to popular belief, their KO brains somehow compensated for the mutation.¿

These counterintuitive results suggested to the co-authors that the enrichment brought about certain changes in the brain cells that allowed them to learn and remember even though lacking the knocked-out NMDA receptors. Electron microscopy showed that the brains of graduates from the enrichment course had more dendritic spines ¿ the minute neural projections on which synapses form.

Whether this apparent mental resurrection can translate from mice to humans, Tsien observed, ¿remains a difficult jump. We must not misinterpret the effects of a rich neighborhood for people.¿ He added: ¿Environment plus genetic influences are both important. So if you¿re stuck with bad genes, don¿t give up. Environment plus training will compensate ¿ to a degree.¿

Enrichment Inspires Virtual Memory Drug

He and his co-authors ¿are now trying to identify all the genes regulated by this behavior of the mice exposed to enriched activities. ¿We have isolated several hundreds of them, and are in the process of further studying their functions. We hope some of the products of these genes could become useful therapeutic targets for treatment of memory disorders.¿

Tsien offered a conceptual example: ¿Say we found a protease the activity of which is downregulated after enriching experience. If the mice play in a Disney World, this enzyme activity goes down. And if that activity happened to correlate with any memory deficiency, you may imagine designing a compound to inhibit that protease. It will achieve a very similar effect to enrichment. That is our current rationale. Also, it will tell us more about the molecular mechanism behind these fascinating phenomena.¿

He continued: ¿Actually, I co-founded a company last month that is temporarily located in San Francisco. It¿s called Eureka Pharmaceuticals Inc., and will collaborate with us in trying to identify all these memory targets. A lot of people,¿ he explained, ¿whether they have brain damage or memory disorder or Alzheimer¿s relatives, all call me and ask if there is some kind of treatment for them. So that suggested to me whether I could team up with industry, which is why we incorporated Eureka.¿

Eureka¿s president, Charles Hsu, told BioWorld Today, ¿We plan to move to a permanent location once we¿ve completed a first round of venture financing. Princeton University,¿ he added, ¿has put some money into Joe¿s intellectual property.¿

On this score, Tsien said, ¿We are very close to final licensing of our patents by the University. Eureka,¿ he added, ¿will target age-related memory processes, using various genomic technologies. They are really going to carry on more of the clinical, practical applications, while I pursue my own interest here in Princeton, which is more of the theoretical fundamentals of how memory works."

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