Johns Hopkins Medicine LogoSaturated fats have a deservedly bad reputation, but Johns Hopkins scientists have found that a sticky lipid occurring naturally at high levels in the brain may prove essential to learning.

The Hopkins team discovered how palmitate, a fatty acid, seems to mark certain brain proteins such as NMDA receptors that require to be activated for long-term memory and learning to occur.

The fatty substance is known to direct the receptors to specific locations in the outer membrane of brain cells thereby sculpting and resculpting novel memory circuits. Also, the outer membrane of brain cells appears to continually strengthen and weaken their connections with each other.

Moreover, the authors reported that this fatty modification could be a reversible process, with some sort of on-off switch, in turn providing possibilities for manipulating it in order to enhance or even, perhaps, erase memory.

“Before now, no one knew that NMDA receptors change in response to the addition of palmitate,” says Richard Huganir, Ph.D., professor and director of the Solomon H. Snyder Department of Neuroscience at Johns Hopkins.

Scientists have known that a brain signaling chemical called glutamate usually activates NMDA receptors which allow two neurons to communicate with one another. However, they were noted to be less certain what allowed this receptor to assemble properly, or what caused it to make its way to the synapse. Synapse is known to be the specialized part of nerve cells where communication takes place.

The discovery was believed to have emerged from work with live neurons in a dish, to which the scientists foremost fed radioactive palmitate, and then separated out the NMDA receptors. They were able to establish that the fat may have attached to the NMDA receptors via tracking radioactivity on X-ray film.

Subsequently, the scientists seemed to have placed both normal and altered NMDA receptors into non-brain cells that don’t usually manufacture their own NMDA receptors. By tracking the radioactive fat, they were able to determine where on the NMDA receptor the fat appears to have attached.

The scientists found that the NMDA receptor seems to undergo ‘dual palmitoylation,’ in two different regions, each of which plays a distinct role in controlling the fate of the receptor inside neurons.

When the fat attaches to the first region, it appears to stabilize the receptor on the surface of neurons. While, when the fat attaches to the second region, the receptors are noted to be accumulated inside neurons, perhaps awaiting a signal to send them to synapses.

“It is rapidly becoming clear that palmitate regulates not only NMDA receptors, but also other brain proteins at work during signaling across synapses,” says Gareth Thomas, Ph.D., a Howard Hughes Medical Institute postdoctoral fellow at Hopkins.

Huganir elucidated that, “This new modification of the NMDA receptor deepens our molecular understanding of how synapses are regulated and how memories might be formed. It also reveals new potential drug targets, such as the enzymes that add or remove the palmitate. If we could shift the balance of the palmitoylation, then perhaps we could affect and enhance learning and memory.”

The study authors believe that this could be part of a quality control measure, assuring that all the Lego-like protein subunits of the receptor are put together correctly.

They further suspected that if palmitoylation fails, the result would be learning and memory impairment because if NMDA receptors fail to make their way to the synapses then communication between neurons may be compromised.

The findings of the study have been published in the journal, Neuron.