Learning and memory shaped by key protein

You're emerging from D Level at the ungodly hour of 5:30 a.m., hoping to catch an hour of sleep before your next final. After a nap that is too short and a shower that is not quite cold enough to wake you up, you get to the test. The first question goes by without a hitch, and the second one too. You flip through the pages, and so far, it doesn't seem too bad, but then you hit that one halting question.

The answer is right there, on the tip of your tongue. You decide to come back to it at the end, but after finishing the entire test, you realize that you just cannot remember the answer. Blame it on the kibra protein.

For years now, neuroscientists have known that the kibra is a scaffolding protein, helping to regulate signaling pathways involved in memory. The kibra is found in both the brain and the kidney; after having initially been labeled with only a number, scientists dubbed the protein with a half-breed name combining "kidney" and "brain." It is believed that the kibra pathway is essential to constructing and maintaining the neuronal circuits that underlie memories.

Thus far, it is known that the kibra pathway works in the membrane trafficking of AMPA-type receptors, which are extremely excitatory. Membrane trafficking refers to the way a protein uses endocytosis to recycle receptors back to the membrane. In addition to its roles in the kidney and the brain, kibra is also thought to function in regulating organ size during early development.

Originally, researchers determined whether people had a certain isoform of kibra and then tested their memory using word recall. Now, at Hopkins, Richard L. Huganir and his lab have further tested the kibra protein. Using mice as test subjects, Huganir has shown that the amount of kibra in the brain affects learning and memory.

"We eliminated this gene in mice and made knockouts, so these mice live and breathe okay, but the physiological process that we study, plasticity and the regulation of receptors, is deficient," Huganir said of their methods. "More importantly, we saw that they learn more slowly, and they have very poor recall the next day while mice with the gene [for kibra] remember very well."

A key term in these trials is plasticity, which refers to how the brain learns from and adapts to its environment. "What we think happens is, when you learn something, a sensory experience comes in, and if it's memorable, pathways are activated and the brain works through 100 billion neurons all communicating with each other that are connected to 10,000 others," Huganir explained. "There are billions, if not quadrillions of synapses. They form neuronal circuits to control behavior and muscle and to make decisions, so when you learn a new memory, it strengthens some connections and decreases some connections to sculpt a neuronal circuit that encodes that memory. Kibra is involved in that process, stabilizing those circuits in rats, mice and humans."

The implications for the future of the kibra protein are infinite. It has been found to be associated with late-onset Alzheimer's disease, a neurodegenerative condition that results in severe memory loss. Huganir believes that with more research, kibra may have a new, therapeutic use.

"Based on work even before our paper came out, a company was started based on kibra to develop drugs to regulate the kibra pathway," he explained. "This was a small biotech startup, but there's no clinical trial yet. With a scaffolding protein, it'll be hard to find a drug to target it." Huganir expressed the need to understand more about the kibra pathway before any drugs can be developed. "There may be other parts of the pathway that can be targeted," he said.

A particularly interesting implication of the kibra protein is its role in people with photographic memories. Huganir and his lab are looking into the possibilities of overexpressing kibra in certain mice. "We know that mice lacking kibra are stupid," said Huganir. "Alternatively, do we overexpress kibra and get a smarter mouse?" He went on to explain that in humans, it is not yet clear what the link is between kibra and intelligence. The difference could refer to a varied amount of kibra or a difference in alternative splicing, which would produce different isoforms of kibra that could affect the ability to remember.

The studies on the genes encoding kibra are still young, and there is much to be done before we see results beyond mice memory tests. However, the future is bright for the kibra protein, and perhaps one day, there will be kibra-based therapies for Alzheimer's patients and possibly the sleep-deprived college students who just can't remember the answer to that one exam question.