Scientists have identified a key molecule responsible for triggering the chemical processes in our brain linked to our formation of memories. The findings, published in the journal Frontiers in Neural Circuits, reveal a new target for therapeutic interventions to reverse the devastating effects of memory loss.
The BBSRC-funded research, led by scientists at the University of Bristol, aimed to better understand the mechanisms that enable us to form memories by studying the molecular changes in the hippocampus — the part of the brain involved in learning.
Previous studies have shown that our ability to learn and form memories is due to an increase in synaptic communication called Long Term Potentiation [LTP]. This communication is initiated through a chemical process triggered by calcium entering brain cells and activating a key enzyme called ‘Ca2+ responsive kinase’ [CaMKII]. Once this protein is activated by calcium it triggers a switch in its own activity enabling it to remain active even after the calcium has gone. This special ability of CaMKII to maintain its own activity has been termed ‘the molecular memory switch’.
Until now, the question still remained as to what triggers this chemical process in our brain that allows us to learn and form long-term memories. The research team, comprising scientists from the University’s School of Physiology and Pharmacology, conducted experiments using the common fruit fly [Drosophila] to analyse and identify the molecular mechanisms behind this switch. Using advanced molecular genetic techniques that allowed them to temporarily inhibit the flies’ memory the team were able to identify a gene called CASK as the synaptic molecule regulating this ‘memory switch’.
Dr James Hodge, the study’s lead author, said: “Fruit flies are remarkably compatible for this type of study as they possess similar neuronal function and neural responses to humans. Although small they are very smart, for instance, they can land on the ceiling and detect that the fruit in your fruit bowl has gone off before you can.”
“In experiments whereby we tested the flies’ learning and memory ability, involving two odours presented to the flies with one associated with a mild shock, we found that around 90 per cent were able to learn the correct choice remembering to avoid the odour associated with the shock. Five lessons of the odour with punishment made the fly remember to avoid that odour for between 24 hours and a week, which is a long time for an insect that only lives a couple of months.”
By localising the function of the key molecules CASK and CaMKII to the flies’ equivalent brain area to the human hippocampus, the team found that the flies lacking these genes showed disrupted memory formation. In repeat memory tests those lacking these key genes were shown to have no ability to remember at three hours (mid-term memory) and 24 hours (long-term memory) although their initial learning or short-term memory wasn’t affected.
Finally, the team introduced a copy of the human CASK gene — it is 80 per cent identical to the fly CASK gene — into the genome of a fly that completely lacked its own CASK gene and was therefore not usually able to remember. The researchers found that flies which had a copy of the human CASK gene could remember like a normal wildtype fly.
Dr Hodge, from the University’s School of Physiology and Pharmacology, said: “Research into memory is particularly important as it gives us our sense of identity, and deficits in learning and memory occur in many diseases, injuries and during aging”.
“CASK’s control of CaMKII ‘molecular memory switch’ is clearly a critical step in how memories are written into neurons in the brain. These findings not only pave the way for to developing new therapies which reverse the effects of memory loss but also prove the compatibility of Drosophila to model these diseases in the lab and screen for new drugs to treat these diseases. Furthermore, this work provides an important insight into how brains have evolved their huge capacity to acquire and store information.”
These findings clearly demonstrate that neuronal function of CASK is conserved between flies and human, validating the use of Drosophila to understand CASK function in both the healthy and diseased brain. Mutations in human CASK gene have been associated with neurological and cognitive defects including severe learning difficulties.
Forgetting caused by brain disease can sometimes be revesed. Alzheimers model rats were made to remember again when given a chemical that breaks down the active forgetting molecule in their brains.
The study published Tuesday in the open access journal PLOS Biology identifies the compound as TC-2153, which prevents the protein STEP (STriatal-Enriched tyrosine Phosphatase) from destroying the brain’s ability to learn and retain new things. STEP was discovered twenty-five years ago by Yale School of Medicine professor and leading author of the study, Dr. Paul Lombroso.
Since that discovery, a number of studies have shown that patients with Alzheimer’s, Parkinson’s, schizophrenia, and fragile x syndrome—the most common known cause of inherited intellectual disability—all have elevated levels of STEP.
The protein STEP attacks neurotransmitters in the brain called glutamate receptors, which allow us to turn short-term memories into long-term memories. This process is critical to learning anything from names, faces, facts, and stories to motor skills, like riding a bike, to spatial information, like the layout of our home.
Several years ago, researchers found that when they genetically lowered STEP levels in mice that were given Alzheimer’s disease genes, the cognitive performance of the sick mice was indistinguishable from that of healthy mice. “This was very exciting,” Lombroso says, “because it suggested that . . . inhibiting STEP’s activity [may] be sufficient” to reverse the cognitive deficits of people with Alzheimer’s.
It’s not viable, however to genetically lower STEP levels in human Alzheimer’s patients. So instead, for the past five years, Lombroso and his colleagues have been using STEP as a “target for drug discovery.” They’ve been sifting through and studying thousands of small molecules, searching for those that would inhibit STEP activity. They finally found one.
As the paper published Tuesday reports, a single dose of the compound TC-2153 was enough to reverse the effects of Alzheimer’s disease in mice. Several cognitive exercises were used in the study to gauge the animals’ ability to learn and remember various motor skills, spatial information, warning signals, and previously seen objects.
One test Lombroso described to Newsweek was the Morris Water Maze. The setup is a basin of water. There is a platform located in one section of the basin, invisible beneath the water’s surface. On the sides of the basin are different symbols (e.g. circle, cross, triangle), which become spatial references that help a mouse placed in the water again and again to eventually learn the location of the platform. Lombroso explains that after a few days of trainings, a healthy mouse knows exactly where the platform is and will swim directly to it. Mice with Alzheimer’s, however, cannot learn, because their excess STEP protein has destroyed the neurotransmitters responsible for turning short-term memories into long-term memories. On the fifth day of training, they’re still swimming around in the water just as lost as they were on the first day.
Amazingly, this study found that, after a dose of the STEP inhibitor, the Alzheimer’s mice were able to learn. In the Morris Water Maze and every other cognitive test, these mice performed just as well as healthy mice. In other words, administration of the compound effectively reversed the cognitive deficits brought on by Alzheimer’s.
Yet much more testing is still required before we can start manufacturing drugs with the TC-2153 compound. Adding a “cautionary note,” Lombroso says, “Many drugs have been successful in the mouse and failed in the humans.” His team is currently trying to replicate the results with other animals, including rats and nonhuman primates.