Why Glutamate Triggers Neuronal Death

Photo: Computer generated image of nerve cells

The researchers disprove an
old theory; © SXC

In many neurodegenerative diseases, a main factor that kills neurons is excessive levels of glutamate, the most abundant excitatory neurotransmitter in many regions of the central nervous system (CNS). Diseases that occur as a result of high glutamate levels include hypoxic–ischemic brain injury (stroke), trauma, seizures, various forms of dementia and neurodegeneration.

For years, the main explanation for the toxic effects of glutamate is that it overexcites neuronal cells via activation of glutamate receptors and thereby kills them. However, clinical trials targeting glutamate receptors have been disappointing suggesting that these receptors play only a minor role in triggering neuronal death.

"The most interesting aspect of our study and the reason we are so excited is that the pathway leading to glutamate-induced nerve cell death involves another vital player – namely, glial cells," says neuroscientist Adriana Di Polo. "Through careful experimentation we now know that glutamate activates signalling pathways in glial cells that then lead to neuronal death."

Glial cells are the most abundant cell type in the nervous system and are traditionally thought of as 'partner' cells to nerve cells providing support, nutrients and an optimal environment. However, this study indicates that glial cells also have a more sinister side that allows them to induce or exacerbate neuronal death in pathological conditions.

The study focused on nerve cells in the retina which convey information from the retina to the brain along the optic nerve, and are the primary link between the retina and the brain. The death of these retinal neurons from excess glutamate causes vision loss in various neurodegenerative disorders including optic neuropathies.

By disrupting signalling events in surrounding glial cells, the researchers were able to protect the majority of these neurons, confirming that glial cell events play a key role in death triggered by glutamate. This new understanding of the excitotoxic cascade of nerve cell death provides targets for successful therapeutic intervention of a wide-range of neurological and neurodegenerative diseases.

MEDICA.de; Source: McGill University