Working memory, the sticky-note reminder system of the brain, holds on to temporarily needed information by forming transient neural networks that keep firing even as the brain ponders other matters. That way the message persists despite distractions. Unless, of course, the network is broken—in which case that mental note to pick up your dry cleaning after work vanishes into your cerebral ether.

After two years of experimentation in three animal models, Yale researchers led by Amy F.T. Arnsten, Ph.D., professor of neurobiology, have identified the molecular mechanism that can make or break a neural network representing a short-term memory. These findings open the door to understanding what causes cognitive function to falter and how to treat several mental disorders.

They found that a molecule called cyclic adenosine monophosphate (cAMP), which accumulates in times of stress and in the brains of persons with certain mental disorders, disconnects the neural networks in the prefrontal cortex by forcing open certain ion channels, much like tripping a circuit breaker to halt the flow of electricity. To keep the networks functioning, these channels, called hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels, must remain closed. They get some help from another type of molecule found next to HCN channels, the alpha 2A adrenoceptor, which, when activated, strengthens the neural networks and keeps them connected by preventing cAMP production.

Alpha 2A adrenoceptors are naturally stimulated by the neurotransmitter norepinephrine, but medications like guanfacine, an antihypertensive agent, also activate them, as the Yale group showed in their paper published in April in the journal Cell. It has long been known that guanfacine can improve the performance of working memory, and the drug is now being used to treat several prefrontal cortical disorders, but how it works has remained a mystery until now. Spurred by intriguing data from the lab of David A. McCormick, Ph.D., professor of neurobiology, the group began to explore the role of HCN channels. “This is an extraordinary example of knowing how a drug works all the way to the level of an ion channel,” said Arnsten.

Excessive HCN channel opening, she said, likely underlies lapses in cognitive function caused by stress, normal aging and several mental disorders, including attention-deficit hyperactivity disorder (ADHD), schizophrenia and bipolar disorder.

With this new finding, researchers can now pursue drug therapies for memory-related disorders involving the prefrontal cortex.