Drugs and stimulating environments reverse memory loss in brain-damaged mice

You swallow the pill. As it works its way through your digestive system, it slowly releases its chemical payload, which travels through your bloodstream to your brain. A biochemical chain reaction begins. Old disused nerve cells spring into action and form new connections with each other. And amazingly, lost memories start to flood back.

The idea of a pill for memory loss sounds like pure science-fiction. But scientists from the Massachussetts Institute for Technology have taken a first important step to making it a reality, at least for mice.

Andre Fischer and colleagues managed to restore lost memories of brain-damaged mice by using a group of drugs called HDAC inhibitors, or by simply putting them in interesting surroundings.

They used a special breed of mouse, engineered to duplicate the symptoms of brain diseases that afflict humans, such as Alzheimer's. The mice go about their lives normally, but if they are given the drug doxycycline, their brains begin to atrophy. The drug switches on a gene called p25 implicated in various neurodegenerative diseases, which triggers a massive loss of nerve cells. The affected become unable to learn simple tasks and lose long-term memories of tasks they had been trained in some weeks earlier.

Fischer moved some of the brain-damaged mice from their usual Spartan cages, to more interesting accommodation. Their new cages were small adventure playgrounds, replete with climbing frames, tunnels and running wheels, together with plentiful food and water. In their new stimulating environments, the mice returned to their normal selves. Their ability to learn improved considerably, and amazingly, seemingly lost memories were resurrected.

They didn't grow any new neurons, and their brains remained the same size. But Fischer found that they did have many more synapses - the connections between nerve cells - than brain-damaged peers. Even though they had lost a substantial number of neurons, their enriched environments triggered the surviving cells to re-wire themselves.

These experiments suggest that many lost memories are in fact not lost at all, but misplaced. The dead neurons take important connections with them and the survivors, though incommunicado, still retain latent traces of memory. When they are jolted into action and form new networks, these trace memories are reinstated. And that provides genuine hope for people affected by dementia, Alzheimer's and other conditions.

It would be a touch silly to suggest putting such people in the equivalent of a large playpen. But Fischer also found a group of drugs called HDAC inhibitors that have the same effect - the molecular equivalent of a stimulating environment.

HDACs or histone deacetylases control whether genes are switched on or off by altering other proteins called histones. DNA winds around histones like spools, which serves to package this long and unwieldy molecule into a compact and more manageable form.

HDACs change the histones so that they wrap more tightly around DNA and render its genetic code unreadable. Any genes contained in these stretches of DNA are silenced. Drugs like sodium butyrate (SB) neutralise HDACs, freeing DNA from the repressive grip of histones.

Any silenced genes can now be freely switched on and among these, are genes that allow the brain's neurons to sprout new synapses. The details still need to be ironed out, but the results are clear - just like mice housed in fun cages, those treated with SB regained lost memories.

Naysayers might point out that these results are all very good for mice, but are a long way off benefiting people. But while our brains outclass those of mice, we appear to store memories in very similar ways. New experienced are initially encoded among the neurons of the hippocampus, only to be transferred into deeper and long-term stores about three or four weeks later.

Four years ago, a man who had been barely conscious for almost 20 years began to move and speak again. His nerves, badly damaged by a car crash, had started to re-wire themselves and form new connections, in the same way that Fischer's rats did. The possibilities are there; it's just the method that needs refinement.

At the moment, the biggest problem with Fischer's approach is that it's akin to shooting at a fly with a shotgun. HDAC inhibitors have far-reaching effects on a multitude of different genes. It's fortunate that these include genes that lead to brain re-wiring, but such a scattershot approach is prone to collateral damage.

Documenting the full actions of HDAC inhibitors is vital. It will allow scientists to understand what side effects such treatments would have in people, while designing more sophisticated drugs with a narrower range of targets.

Reference: Fischer, Sananbenesi, Wang, Dobbin & Tsai. 2007. Recovery of learning and memory is associated with chromatin remodelling. Nature doi:10.1038/nature05772

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