Volume 85 Issue 36 | Web Exclusive
Issue Date: September 3, 2007

Cover Stories: Hold That Thought

The Well-Endowed Mind

Brainy mice and mice with mental deficits reveal reasons for the differences between good and poor memory
Department: Science & Technology | Collection: Life Sciences
University of Texas Southwestern Medical???s Powell (from left), Bibb, and Donald Cooper showed that deleting the enzyme Cdk5 made mice smarter.
Credit: UT Southwestern Medical Center
University of Texas Southwestern Medical???s Powell (from left), Bibb, and Donald Cooper showed that deleting the enzyme Cdk5 made mice smarter.
Credit: UT Southwestern Medical Center

What distinguishes a person with a good memory from one with a poor memory?

The ravages of Alzheimer's or other neurodegenerative diseases can explain some memory deficits. Amnesia caused by emotional trauma or physical damage to the brain can also impair memory.

But if disease or damage isn't a factor, "there are probably going to be many subtle differences" between people with good and bad memory, says Craig M. Powell, a neurologist at the University of Texas Southwestern Medical Center.

Dozens of neurochemical signaling pathways and numerous molecules and genes are linked with memory, says Alcino J. Silva, a neurobiologist at the University of California, Los Angeles. "There are at least 150 genes that have been implicated in memory," he adds. "Changes in any one of these genes could easily account for why some individuals learn better than others."

Different genetic alleles that produce slightly different versions of brain-derived neurotrophic factors result in measurable differences in memory performance among humans, notes Tim Tully, a neuroscience professor who studies memory at Cold Spring Harbor Laboratory, in New York.

Likewise, Tully says, "it's reasonable to assume that some people have enhanced memory consolidation capacity because they carry a 'good allele' for one of the proteins in the pathway controlled by the transcription factor CREB." CREB, cAMP response element-binding protein, helps orchestrate memory consolidation, the process by which recent memories are converted to long-term ones. "And there could be people with less than great memory consolidation capabilities because they have a 'bad allele' for one of the proteins in this pathway." A good allele might boost CREB production, for instance.

In fact, Tully discovered in 1995 that genetically increasing CREB expression in fruit flies supercharged their memory. Where normal flies required 10 training sessions to remember an association between an odor and a foot shock, the mutated flies needed just one session. "That's the functional equivalent of people with photographic memories," Tully says. He notes that such people "can commit information to long-term memory with very little practice."

Another group of people—the so-called savants—demonstrates a particular strength in one area of memory, though in some respects, "they are dysfunctional in human society," Powell notes. "An autistic savant, for example, may have normal or even superior intelligence but limited social skills."

Observations of mice that display some of the features of autism lead Powell to suspect that the connections between neurons, also known as synapses, "function differently in autism, breaking down higher order cortical function that requires a lot of cooperation between brain areas through multiple synapses. A small change in synaptic function that might favor learning and memory of a certain type may in a higher level activity be deleterious."

Researchers have demonstrated that memory and intelligence can be improved genetically, creating more than a dozen varieties of "smart" mice. In 1999, Joe Z. Tsien, now a pharmacology and biomedical engineering professor at Boston University, created mice with better memory than normal. He modified the mice to express a form of the NMDA (N-methyl-D-aspartate) receptor that can pass more calcium into neurons. That modification leads to greater long-term potentiation, the collection of synaptic changes that serves as the basis for enduring memories.

More recently, Powell and his Southwestern Medical colleague James A. Bibb reported that knocking out the gene for cyclin-dependent kinase 5 (Cdk5) enhances synaptic plasticity and memory performance in mice (Nat. Neurosci. 2007, 10, 880). The technique interfered with Cdk5's normal role in breaking down NMDA receptors.

By genetically reducing the activity of eIF2α, a protein that suppresses CREB activity and regulates RNA translation rates, McGill University's Nahum Sonenberg and Mauro Costa-Mattioli created their own smart mouse (Cell 2007, 129, 195). "Because the mouse has better memory, we can now think about drugs to mimic this mutation," Sonenberg says. He is hunting for small molecules that can bind to eIF2a and inactivate it.

Other researchers have already found compounds that can assist memory and learning in mice. For instance, Tully used a phosphodiesterase (PDE) inhibitor to cure memory impairment in a mouse model of Rubinstein-Taybi syndrome, which causes mental retardation in humans. PDE inhibitors improve memory consolidation by increasing CREB activation.

Silva found that the cholesterol drug lovastatin reverses learning disability in a mouse model of the genetic condition neurofibromatosis type 1. The compound is in clinical trials for patients with the disease.

Now that researchers know that at least some types of retardation are caused by biochemical rather than developmental abnormalities, "the possibility is open to find small molecules that can modulate that abnormality back to normality" in humans, Tully says.

Indeed, the ability to manipulate biology to enhance cognition represents a tremendous opportunity from both a scientific and business perspective, according to Silva. "If you look at the number one cause of disease and disability for which we have the least number of treatments, I think it's cognitive disorders," he says.

Cognitive disorders are associated with illnesses ranging from cancer to schizophrenia to Parkinson's disease. But Silva notes that it won't be feasible to trace the cause and develop a targeted treatment for every disease associated with cognitive deficits. Instead, he says, "we hope that we may be able to develop nonspecific treatments to address the hundreds of disorders that affect cognitive function in millions of people worldwide."

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