How to Build a Doogie

Now that investigators have found out quite a bit about both direct and modulatory processes involved in learning and memory, attempts are being made to improve some of these processes. Many changes impair learning and memory—for example, blockage of protein kinases, reduction in CREB, or inhibition of protein synthesis. Can other changes improve learning and memory? We’ll consider an example of a change in the NMDA receptor that is implicated in some kinds of learning.

The NMDA receptor (NR) consists of the core NR1 subunit and NR2 subunits. The NR2 subunits determine the length of time that the NR channel is open to Ca2+ and thus the size of the excitatory postsynaptic potential (EPSP). Young animals express predominantly NR2B subunits, which allow longer Ca2+ conduction and thus larger EPSPs. The number of these subunits is down-regulated in the transition from juvenile to adult, and shorter-acting NR2A units come to predominate.

Joe Z. Tsien and coworkers (Y. P. Tang et al., 1999) prepared transgenic mice in which larger-than-normal numbers of juvenile NR2B subunits are expressed, especially in the cerebral cortex and the hippocampus. These animals showed normal growth and body weights and mated normally. Analysis of the hippocampal neurons in transgenic versus wild-type mice revealed that the transgenic mice had greater numbers of NR2B subunits per synapse and about fourfold greater flow of Ca2+ during activation. Hippocampal slices from transgenic mice showed enhanced LTP but no difference in LTD compared to wild-type mice.

At 3 to 6 months of age, transgenic mice were compared with wild-type mice in a variety of behavioral tasks. In examining a novel object rather than a familiar object (Figure 1)—a test that requires the hippocampus—all mice showed equal amounts of initial exploration of the objects, and all showed equal preference for the novel object 1 hour later. When tested 1 day or 3 days later, however, transgenic mice exhibited significantly stronger preference for the novel object than did the wild-type mice, thus showing stronger long-term memory.

Figure 1 Presented with two objects, a smart mouse will spend more time investigating the one it hasn’t seen before.

In two forms of associative emotional memory, the transgenic mice learned more strongly than the wild-type mice. The mice were tested for extinction of the fear response by repeated exposure to a neutral environment without shock. Although the transgenic mice showed greater fear responses early in the tests, they extinguished the fear responses more rapidly than the wild-type mice did. In the Morris hidden-platform water maze—a test known to require activation of NMDA receptors in the hippocampus—both the transgenic and the wild-type mice learned, but the transgenic mice learned faster.

The investigators propose that their research indicates a potential new direction for treatment of disorders of learning and memory and “a promising strategy for creation of other genetically modified mammals with enhanced intelligence and memory” (Y. P. Tang et al., 1999, p. 69). They showed their enthusiasm by naming their transgenic mice Doogies after the teenage genius in the television show Doogie Howser, M.D.

These findings certainly indicate that the NMDA receptor is involved in several kinds of learning. Whether the findings will help treat disorders of learning and memory is less sure. Humans have an NR2B gene nearly identical to that in mice, but some neuroscientists worry that a drug that increases NMDA receptor activation could have undesirable side effects, such as increased risk of epilepsy or stroke. In fact, the genetic manipulation that made the Doogie mice smarter also caused them to experience chronic pain longer than control mice (Wei et al., 2001).

Others wonder whether general enhancement of learning and intelligence is a good idea socially. Tim Tully, a member of a group that in 1995 announced genetic improvement of long-term memory in Drosophila by inducing the activation of a form of CREB (J. C. Yin et al., 1995), suggested that we may have evolved to learn less rapidly in maturity to prevent overloading of the brain’s memory capacity. Joe Tsien prefers to think that the decrease in learning with age is evolutionarily adaptive for the population because it reduces the possibility that older individuals—who may have already reproduced—will compete successfully against younger ones for resources such as food. This debate shows no prospects of quick resolution.

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