People with epilepsy often have memory problems. Among other things, they find it difficult to distinguish between the known and the unknown. With the help of experiments with mice, researchers have now uncovered which mechanisms could possibly be behind it. Accordingly, in epilepsy, certain cells in the brain are too easily excited, so that they react non-specifically to both known and unknown stimuli. In the mouse model, the researchers were already able to alleviate the symptoms with medication. The findings may also provide new therapeutic approaches for human patients.
Every place we visit has a distinctive combination of characteristics that help us recognize it when we visit again. The apple tree in front of the house, the clinker facade, the red-painted fence – our brain saves all of this and links it to this place. However, in people with epilepsy, this type of memory is disrupted. Among various other memory problems, they have difficulty remembering whether they have seen a place or an object before. While scientists fundamentally assume that both structural changes in the brain and the epileptic seizures themselves play a role in memory lapses, the exact mechanisms have so far been little researched.
How places are remembered
A team led by Nicola Masala from the University of Bonn has now researched how the processing of stimuli and memory works in the brains of mice in which the team had artificially created epilepsy. They focused on the hippocampus, a region in the brain that plays a central role in memory, including spatial recall. "There are so-called place cells in the hippocampus," explains Masala. "These help us to remember places we have visited." These place cells store certain characteristics of a visited place. If they are activated again by the same stimuli, this awakens the memory of having seen this place before.
Each place cell has a large number of long extensions, the dendrites. Via numerous contact points, so-called synapses, on these dendrites, these brain cells collect information that is passed on in the form of electrical potentials. With sufficiently strong stimuli, ion channels are opened through which positively charged sodium ions can flow into the cell. The information is calculated using a process known as dendritic integration: only if a sufficient number of signals are received at the same time can a strong voltage pulse form in the dendrite – a so-called dendritic spike. Figuratively speaking, the activation in the healthy brain only takes place if the information for the apple tree, brick wall and red fence is received at the same time.
Mice with memory impairments
"However, this process is disturbed in mice with epilepsy," explains Masala's colleague Heinz Beck. “In them, the spikes already occur when only a few synapses are stimulated. The stimulation doesn't have to occur at exactly the same time either.” In the researchers' experiments, mice with epilepsy were therefore unable to tell whether they had seen a place or an object before.
This was shown, among other things, in an experiment in which the animals were first accustomed to the fact that there were two blue lids in a cage. After a few days, one of the lids was exchanged for a clear Petri dish of the same size. To find out whether the mice recognized the Petri dish as new, Masala and her colleagues measured how long the mice sniffed at the familiar blue lid and the unfamiliar Petri dish. The result: While mice from the control group explored the petri dish longer than the blue lid, the epileptic mice made no distinction between the two objects. In a similar experiment on a treadmill, they also showed no sign of recognizing familiar locations.
Drug approaches
To find out why, the researchers used fluorescent markers to observe the activation of nerve cells in the mice brains. After the experiments were completed, the animals were also decapitated and their brains examined. Masala and her colleagues found that a certain type of sodium ion channel was present in the brains of the epilepsy mice much more frequently than normal. "As a result, even a few poorly synchronized stimuli at the synapses are sufficient to open many channels and cause a spike," explains Masala's colleague Tony Kelly.
On a group of epilepsy mice, the researchers have already tested how the memory problems could possibly be treated with medication. To do this, they administered an inhibitor to the animals that specifically blocked the affected channel type. "As a result, the firing behavior of the dendrites normalized in them. In addition, they could better remember places they had visited,” reports Masala. If similar mechanisms play a role in human epilepsy patients, the findings could possibly help in the long term to develop drugs that improve the memory of those affected.
Source: Nicole Masala (University of Bonn) et al., Brain, doi: 10.1093/brain/awac455