Immune Molecules Promote Memory Formation: Study

By Anette Breindl

Science Editor

Researchers have discovered that two proteins best known for their roles in fighting infection play a role in cognitive processes, in particular in memory formation. The double-stranded RNA-activated protein kinase, or PKR, and interferon gamma "are controlling, in the brain, the kind of processes that lead to memory formation," Mauro Costa-Mattioli told BioWorld Today.

Costa-Mattioli is an assistant professor of neuroscience at the Baylor College of Medicine and the senior author of the paper describing the studies, which appeared in the Dec. 9, 2011, issue of Cell.

PKR, he said, "was originally discovered to be activated in response to viral infections." But its activity is also increased in a broad variety of brain disorders with cognitive components, including Alzheimer's, Parkinson's and Huntington's.

"For me, it was very difficult to conceive that all those disorders would mimic a viral infection," he said. And so his lab set out to look at whether PKR played a more direct role in the brain.

Costa-Mattioli, first author Ping Jun Zhu and their colleagues started by knocking out PKR in mice and then looking at those animals' brain rhythms via EEG recordings. They found that PKR had more highly synchronized, or rhythmic, brain firing.

The researchers next looked at how neural transmission differed between PKR knockouts and their wild-type cousins in more detail, testing the brain's responses to electrical pulses to work out how neural connections were altered to produce greater synchronicity. They found that PKR knockouts had weaker inhibitory signaling of the neurotransmitter GABA than control mice.

Critically, PKR inhibition made it easier to induce so-called late long-term potentiation, or LTP, which reflects changes in the strength of synaptic connections underlying memory storage. Mice lacking PKR developed LTP more easily than their wild-type counterparts, which means they were able to physically encode memory traces more easily.

Based on the results, Costa-Mattioli and his team next tested PKR knockouts in several learning experiments. They found that the knockouts were better able to remember both a location where they could escape from water, and where they had received a shock.

Treatment with a PKR inhibitor not only decreased inhibitory signaling but also enhanced LTP and long-term memory storage.

Mechanistically, inhibiting PKR increases the level of interferon-gamma, which is itself a major immune signaling molecule. Interferon gamma, in turn, reduced inhibitory GABA signaling. Indeed, unlike in control mice, the PKR inhibitor had no effects on neural signaling or memory performance in interferon-gamma knockouts, demonstrating that its action is mediated by interferon gamma.

Costa-Mattioli and his team ultimately would like to harness PKR inhibition clinically. Because PKR signaling is increased in many neurological disorders, his team is looking at different animal models of disease to see where the results of PKR inhibition look most promising.

He said PKR inhibition might also be able to fight milder age-related memory decline. Most elderly "are not demented," he said. "But let me tell you, they would welcome a drug which would delay the memory decline that accompanies aging."

In fact, he said, the increased synchronicity in firing that results from PKR inhibition may lead to overall cognitive enhancement – that is, it may increase intelligence and cognitive performance.

Intelligence, of course, is a vague and contested concept even in humans, and to show experimentally that a mouse has become more "intelligent" is almost impossible. But there are a number of people who are considered highly intelligent that have also had seizures – including, among others, leaders from Julius Cesar to Harriet Tubman, as well as writers such as Charles Dickens and Fyodor Dostoyevsky.

"Historically, this relationship between seizures and extraordinary mental abilities has fascinated many scholars," Costa-Mattioli noted. However, little to nothing is known about the possible genetic mutations associated with that unusual type of epilepsy. PKR could be the first concrete example of such a mutation.

And though strong epilepsy is clearly a health problem, technically speaking, "the definition of seizures is a bunch of neurons firing in a synchronized manner," Costa-Mattioli said. "There is no clinical manifestation" – that is, convulsions – "that we can see in these animals but their memory is enhanced; is that not cool?"

Still, he acknowledged, some people might get queasy at the notion of inducing neuronal excitability through PKR inhibition, whether or not it appears to be behaviorally benign. But he noted that his team saw electrographic seizures only in the knockouts, which had no PKR signaling at all; treatment with the inhibitor did not appear to lead to electrographic seizures but still promoted brain rhythms.

That said, in neural disorders, the risk should be very low, because "in all those disorders, PKR activity is reduced. . . . All we hope to do is bring its activity back to normal. Whether this manipulation can restore normal memory function in these cognitive disorders remains to be seen."