Crucial enzyme changes memory-making abilities of mice

Canadian researchers have taken a step towards developing a pill that could improve memory by pinpointing and testing a potential target enzyme in the brain. 

Nahum Sonenberg and his colleagues at McGill University in Montreal, tested genetically engineered mice that lacked a molecular trigger called elF2


. This initiation factor is responsible for translating the genetic information held in RNA to build a particular protein.

The team found that when the factor was phosphorylated, the mice were unable to make new long-terms memories. This suggests that blocking phosphorylation should improve memory formation.

Memories are made of this

The physiological basis of this memory formation is known as long term potentiation (LTP). It involves the strengthening of synapses - the junctions between neurons - as something new is learned and stored as a memory. For example, if one recites a speech or a poem, a specific sequence of neurons fire repeatedly. After sufficient practice, the repeated firing causes the connections between these neurons to grow stronger, making it possible to recite the words from memory. 

Sonenberg explains that these long term ’plastic’ changes in neurons, which enable us to memorise, require the production of specific proteins. Put simply, some proteins help build new memories and some inhibit them, and that’s where elF2


comes in. 

’When elF2


is phosphorylated it stimulates the translation, or production, of another protein called ATF4 which inhibits these plastic changes in the synapse,’ he told Chemistry World. ’In our mice, if elF2


   phosphorylation is reduced we see a corresponding increase in their ability to learn.’ 

The mice’s learning and memory skills were put to the test in a number of behavioural experiments, including a water maze test, where the mouse’s spatial memory is gauged by its ability to remember the location of a raised platform in a pool of water. 

We showed in these tests that this is indeed a smarter mouse,’ Sonenberg told Chemistry World. ’We also carried out electrophysiology, stimulating the neurons, and were able to physically measure the increased strength of the synapses.’ 

To begin their search for a chemical memory-booster, Sonenberg’s team treated the mice with a molecule that increases the phosphorylation of elF2


. They saw a corresponding decrease in performance in their previously ’smarter’ mouse.  

’The beauty of this is that we are going from memory to molecules. I’m sure that will be the future of this field,’ said Sonenberg. ’Now we have a target we can play with. We already have a drug that effectively stimulates this phosphorylation, so we are now looking for one that has the opposite effect.’

Memory trouble 

Christian Holscher from Ulster University in the UK urges caution when talking about memory enhancers. He told Chemistry World that such drugs have been talked about for decades but, so far, have remained elusive. 

’Upregulating memory has a lot of potential drawbacks,’ he said. ’If neuronal excitability is upregulated, it could affect a number of other physiological processes, like causing toxicity by over-activation of synapses. You have to consider, how would the drug fare if it was taken by a 56 year old overweight manager with high blood pressure and an alcohol problem?’

Holscher also pointed out that the delicate balance of remembering and forgetting is an important part of the function of our memory, adding, ’the reason why we forget is because 99 per cent of the information we get every day is not worth memorising. If we did remember every detail, our brain would be swamped very quickly with irrelevant information.’ 

But he agrees that revealing the intricacies of the complex biochemical pathways involved in memory formation, although a long way away from a tangible treatment, is an important step forward. 

Victoria Gill