When incoming signals to the pyramidal tract build to high intensity, pyramidal cells adapt by becoming more inclined to fire than they normally are. This phenomenon, which neuroscientists call plasticity, is thought to underpin learning and memory. It ensures that volleys of high-intensity input — such as might accompany falling into a hole, burning one’s finger with a match, suddenly remembering where you buried the treasure or learning for the first time how to spell “cat” — are firmly stored in the brain’s memory vaults and more accessible to retrieval.

These intense bursts of incoming signals are the exception, not the rule. Pyramidal nerve cells constantly receive random beeps and burps from upstream nerve cells — effectively, noise in a highly complex, electrochemical signaling system. This calls for some quality control. Pyramidal cells are encouraged to ignore mere noise by another set of “wet blanket” nerve cells called interneurons. Like the proverbial spouse reading a newspaper at the kitchen table, interneurons continuously discourage pyramidal cells’ transmission of impulses to downstream nerve cells by steadily secreting an inhibitory substance — the molecular equivalent of yawning, eye-rolling and oft-muttered suggestions that this or that chatter is really not worth repeating to the world at large, so why not just shut up.

Passing along the message

But when the news is particularly significant, pyramidal cells squirt out their own “no, this is important, you shut up!” chemical — endocannabinoids — which bind to specialized receptors on the hippocampal interneurons, temporarily suppressing them and allowing impulses to continue coursing along the pyramidal cells to their follow-on peers.

A-beta is known to impair pyramidal-cell plasticity. But Madison’s research team showed for the first time how it does so. Small clusters consisting of just a few A-beta molecules render the interneuron’s endocannabinoid receptors powerless, leaving inhibition intact even in the face of important news and thus squashing plasticity.

While small A-beta clusters have been known for a decade to be toxic to nerve cells, this toxicity requires relatively long-term exposure, said Madison. The endocannabinoid-nullifying effect the new study revealed is much more transient. A possible physiological role for A-beta in the normal, healthy brain, he said, is that of supplying that organ’s sophisticated circuits with yet another, beneficial layer of discretion in processing information. Madison thinks this normal, everyday A-beta mechanism run wild may represent an entry point to the progressive and destructive stages of Alzheimer’s disease.

Exactly how A-beta blocks endocannabinoids’ action is not yet known. But, Madison’s group demonstrated, A-beta doesn’t stop them from reaching and binding to their receptors on interneurons. Rather, it interferes with something that binding ordinarily generates. (By analogy, turning the key in your car’s ignition switch won’t do much good if your battery is dead.)

Exposure to marijuana over minutes or hours is different: more like enhancing everything indiscriminately, so you lose the filtering effect.

Madison said it would be wildly off the mark to assume that, just because A-beta interferes with a valuable neurophysiological process mediated by endocannabinoids, smoking pot would be a great way to counter or prevent A-beta’s nefarious effects on memory and learning ability. Smoking or ingesting marijuana results in long-acting inhibition of interneurons by the herb’s active chemical, tetrahydrocannabinol. That is vastly different from short-acting endocannabinoid bursts precisely timed to occur only when a signal is truly worthy of attention.

“Endocannabinoids in the brain are very transient and act only when important inputs come in,” said Madison, who is also a member of the interdisciplinary Stanford Bio-X institute. “Exposure to marijuana over minutes or hours is different: more like enhancing everything indiscriminately, so you lose the filtering effect. It’s like listening to five radio stations at once.”

Besides, flooding the brain with external cannabinoids induces tolerance — it may reduce the number of endocannabinoid receptors on interneurons, impeding endocannabinoids’ ability to do their crucial job of opening the gates of learning and memory.

The study’s lead author was postdoctoral scholar Adrienne Orr, PhD. Other co-authors were postdoctoral scholars Jesse Hanson, PhD (now at Genentech) and Dong Li, PhD; and former undergraduate Adam Klotz, now a student at Stanford’s Graduate School of Business. The study was funded by the National Institute for Mental Health (grant MH065541), the Harold and Leila Y. Mathers Charitable Foundation and Elan Pharmaceuticals.

Information about Stanford’s Department of Molecular and Cellular Physiology, which also supported this work, is available at http://mcp.stanford.edu/.