[Epilepsy Research UK]
Neurons communicate with each other via chemical messengers known as neurotransmitters, which are either excitatory or inhibitory. An excitatory neurotransmitter causes the ’next’ neuron to fire an electrical signal, whilst an inhibitory one causes it remain inactive. The major excitatory and inhibitory neurotransmitters in the brain are known as glutamate and GABA respectively, and a fine balance between the two must be maintained for normal brain function to occur. In epilepsy there is too much excitation in the brain, and this can be a result of excess glutamate or insufficient GABA. In both cases neurons are at risk of becoming hyperexcitable and seizures can result.
The neurons in the adult brain do not divide, and it was previously thought that they could not regenerate. In 1989, however, a scientist in New York identified immature cells in the brains of adult mice that were self-renewing and could develop into various brain cell types, including neurons, depending upon their environment. These are known as neural stem cells (NSCs) and they are found in very few regions of the brain including the hippocampus.
NSCs can be extracted from the brain and cultured in the laboratory, where they grow and divide readily. By varying the culture media used, scientists are able to control the type of cells that the NSCs will develop into, and it is now even possible to influence whether an excitatory neuron or an inhibitory one is generated.
In previous studies, researchers tried to engineer NSCs to develop into inhibitory (GABA-producing) neurons. They then transplanted the cells into the brains of epileptic animals in the hope that the increase in GABA would dampen neuronal excitation and curb the animals’ seizures. A successful outcome would have given hope for NSC therapy as a prospective epilepsy treatment; however unfortunately it failed. This was largely due to the low survival rate of the NSCs following transplantation, but also because it couldn’t be guaranteed that the NSCs would develop into inhibitory neurons once they had been transplanted.
Scientists at the University of California have now discovered that other immature cells known as medial ganglionic eminence cells have the potential to succeed where NSCs have failed. The ganglionic eminence is a temporary structure that is present in the developing embryonic and foetal brain. It is made up of three sections – medial, lateral and caudal – and it is responsible for producing inhibitory neurons and support cells and directing them to the correct part of the brain. Most medial ganglionic eminence cells (which will now be referred to as MGECs) are destined to become a particular type of neuron known as an interneuron, which provide controlled inhibition to neuronal networks.
MGECs are not found in the adult brain; however the researchers in California managed to generate MGE-like cells in the laboratory using two types of human stem cell. When they transplanted the cultured cells into the brains of mice (a strain that does not reject human tissue), they found that the cells not only survived, but that they formed connections with the rodents’ natural brain cells and matured into specialised interneurons. In a recent publication, the scientists noted that the development of the MGE-like cells within the mouse brains very closely mimicked that which occurs in human development.
In another stage of the study, the team worked with mice that had a severe, drug-resistant form of epilepsy that resembles human mesial temporal lobe epilepsy (in which seizures are thought to originate in the hippocampus – an important memory centre in the brain). The group transplanted cultured MGE-like cells into the hippocampi of these mice and closely monitored their seizure activity. By 9 months post-transplantation, they found that seizures had been abolished in 50% of the mice, and that the remaining animals were experiencing far fewer spontaneous seizures than before.
These findings are extremely exciting because they are the first to report a curbing of seizures following cell transplantation. This study has also shown that the cells in question – MGE-like cells – can be generated in the laboratory. A lot more research is needed before this becomes a viable therapy in humans; however if it does prove successful, it could potentially become a revolutionary treatment for people with drug-resistant epilepsy. One of the challenges that the researchers note, is that it takes up to nine months for MGE-like cells to mature into inhibitory interneurons. Their next step is to explore whether this maturation period can be accelerated, to enable a more rapid treatment response. We very much look forward to hearing the results of their investigations.