Star-shaped brain cells feed long-term memory

Star-shaped cells in our brains called astrocytes were once considered little more than structures to fill the gaps between all-important neurones. But more recent evidence has emerged to reveal that those astrocytes play more than a supporting role; they are involved in information processing and signal transmission and they help to regulate the shapes of our neurones and their connections to one another.

Now, researchers reporting in the March 4th Cell, a Cell Press publication, have found that astrocytes are also essential for making long-term memories. When they don't function properly, rats develop amnesia.

More specifically, the new findings show that long-term memory formation depends on the delivery of lactate, an energy source derived from glycogen (a stored form of glucose), from astrocytes into neurones. If that transfer is blocked in any number of ways, rats fail to remember events that happened days or a week before. Their short-term memory, on the other hand, is unharmed.

'This is a novel way to think about how the brain works in making memories, and long-term memories in particular,' said Cristina Alberini of Mount Sinai School of Medicine.

Scientists used to think it was all about changes to neuronal networks. 'But that explanation simply isn't sufficient anymore,' she said. 'You need astrocytes and perhaps other cells as well; it's not just neurones.'

There had been hints that astrocytes might have an important role to play in memory. Studies have shown that spatial learning and working memory in rats leads to an increase in the number of astrocytes. Learning in young chicks also depends on the breakdown of glycogen, a process known to occur in astrocytes and not in neurones.

Alberini teamed up some years ago with Pierre Magistretti of Ecole Polytechnique Federale de Lausanne. His group had proposed that neurones and astrocytes might be linked through what they referred to as metabolic coupling, involving the transfer of lactate derived from glycogen from one cell type to the other.

Alberini's group had a perfect model for testing that idea in rats. Her team studies long-term memory and the underlying changes in the brain responsible by exposing rats to a single unpleasant experience - namely a footshock. After just one event, rats will form a lasting memory of the place where that footshock was delivered and avoid it. That avoidance behaviour offers a way to measure the memory.

'When events are emotionally charged, we remember them much better,' Alberini said.

Her group knows a lot about the changes that such a learning event produce in neurones of the hippocampus, a region of the brain that is central to learning and memory.

It's also clear that long-term memory and short-term memory are distinct, she explained. Short-term memory relies on modifications to proteins that are already present. Long-term memory depends on new protein synthesis and changes in gene expression that lead to a change in the structure of synapses, the connections from one neurone to another.

Now, Alberini and her colleagues report that in the rat hippocampus learning leads to a significant increase in extracellular lactate levels derived from glycogen stored in the astrocytes. That breakdown of lactate is essential for long-term but not short-term memory formation. In the absence of glycogen breakdown, rats initially remembered their negative experience, but by a day later they had forgotten. When rats were retested days later, their memory loss persisted.

Rats also developed amnesia when the lactate transporters on either their astrocytes or neurones were disrupted. When lactate was delivered straight to the brains of rats whose transport of lactate out of astrocytes was blocked, their ability to remember things in the long-term was restored. Interestingly, glucose, an alternative energy source, didn't work quite so well.

'Lactate must do something different or more efficiently,' Alberini said. It's possible that lactate might be more than just an energy source, she says, an idea she plans to explore in further studies.

The findings not only shed light on how long-term memories are formed, but they may also have important implications for neurodegenerative diseases such as Alzheimer's and Parkinson's disease or the memory loss that simply comes with age.

'Those conditions often involve the loss of synaptic functions,' Alberini said. 'If this is a mechanism [for long-term memory formation] it opens up new avenues for investigation.' Her team will look to animal models of degenerative diseases to see whether there is any evidence that the astrocyte-neuron lactate transport system may be disrupted.