Arches. Photo by Daniel Chia
HOPES: Huntington's Outreach Project for Education, at Stanford
Jun
26
2011

About Glutamate Toxicity

Glutamate is a powerful excitatory neurotransmitter that is released by nerve cells in the brain. It is responsible for sending signals between nerve cells, and under normal conditions it plays an important role in learning and memory. There are two general ways, however, that glutamate can actually be damaging to nerve cells and the brain as a whole. First, there can be too much glutamate around; abnormally high concentrations of glutamate can lead to overexcitation of the receiving nerve cell. Second, the receptors for glutamate on the receiving nerve cell can be oversensitive, such that less glutamate molecules are necessary to excite that cell.

In both cases, cells activated by glutamate become overexcited. This overexcitation can lead to effects that can cause cell damage and/or death. For this reason, glutamate is referred to as an excitotoxin when it causes cellular damage. Scientists have found that certain glutamate receptors in the nerve cells of patients with HD tend to be oversensitive to glutamate. For some patients with HD, glutamate can act as an excitotoxin, even if its levels are not particularly high. Treatments that attempt to inhibit glutamate activity therefore may have some therapeutic potential.

Neurotransmitters like glutamate are responsible for nerve signaling—that is, for passing chemical messages from one nerve cell to another. Glutamate, an excitatory neurotransmitter, is believed to be involved in the death of nerve cells of people with HD. At normal concentrations, glutamate is crucial for brain functions such as learning and memory. However, at high concentrations the increased cellular activity caused by glutamate results in over-excitation of nerve cells, which eventually leads to cell death. When glutamate causes cellular damage, it becomes an excitotoxin, and the theory by which glutamate damages cells is called the Excitotoxicity Theory. (For more on glutamate, click here).

Excitotoxicity Theory^

Glutamate exerts its effects by binding to specific receptors on nerve cells. There are various types of glutamate receptors. Here we will concern ourselves with two types of glutamate receptors, which are called the NMDA receptor and the non-NMDA receptor. These receptors all contain glutamate-binding sites. Once glutamate binds to the receptor, glutamate “excites” the cells by causing positive ions to flow into the cell, increasing the cell’s electrical charge. The increased charge triggers changes in the neuron that ultimately result in the release of many neurotransmitters at the end of the cell.

Scientists have discovered that NMDA receptors in cells of people with HD are overactivated by glutamate. Researchers believe that this overactivation is due to the impairments in energy metabolism caused by the altered huntingtin gene of people with HD. (For more on energy metabolism, click here.) The defect in energy metabolism results in a decreased amount of energy in the cell, leading to changes in the NMDA receptor.

Fig L-1: NMDA & Non-NMDA Receptors

The NMDA receptor on nerve cells is unique in that it has various properties not found in other types of receptors. First, the NMDA receptors have the special ability to let in large amounts of calcium ions (Ca2+), an important mediator of glutamate’s toxic effects in HD patients. Non-NMDA receptors do not allow the entry of Ca2+. We will talk more about the destructive effects of Ca2+ later in this section. A second important property of the NMDA receptor is that its opening is blocked by a single magnesium ion (Mg2+). An Mg2+ ion is removed only when the electrical charge inside the cell rises to a specific value. While non-NMDA receptors open any time glutamate binds to them, the NMDA receptor needs both the binding of glutamate and an increase in cell charge before it opens.

Normally, as glutamate is released by “messenger-sending” nerve cells, it binds to the NMDA and non-NMDA receptors of the receiving nerve cell. Because the non-NMDA receptors are not blocked, the binding of glutamate alone opens these receptors and allows positively charged ions to flow into the cell. Ion pumps present in the cells remove some of the positive ions, preventing the charge inside the cell from rising too quickly. These ion pumps will only work if there is sufficient amount of energy in the cell. Because of the activities of these ion pumps, a lot of glutamate molecules have to bind to the non-NMDA receptors before the cell’s charge rises to the value that will allow the Mg2+ ion of the NMDA receptor to be removed. Once the Mg2+ ion is removed, the NMDA receptor allows Ca2+ ions to flow in.

Fig L-2: Ca2+ Entry into the Cell

In HD nerve cells, in contrast, the lower amount of energy available reduces the ability of the ion pumps to prevent a rapid increase in cell voltage. As a result, fewer glutamate molecules binding to the non-NMDA receptors are needed to increase the cell charge to the value needed to remove Mg2+. The premature unblocking of the NMDA receptor causes an increase in the entry of Ca2+ ions into the cell. As Ca2+ comes rushing into the cell, it activates various molecules that are capable of degrading essential proteins and cellular membranes, increasing the number of free radicals inside the cell, and causing further increases in the amount of Ca2+ inside the cell. Cell death eventually results from the combination of these effects that result from the increased Ca2+ entry.

In summary, the altered huntingtin protein causes a decrease in the nerve cell’s energy supply. This lack of energy results in an increase in the sensitivity of NMDA receptors to glutamate molecules. As the NMDA receptors become over-activated, more Ca2+ ions are able to enter the cell. The entry of Ca2+ results in the activation of various molecules that are capable of causing cell death.

Anti-glutamate therapies include drugs and supplements that are capable of reducing these various effects of glutamate in cells. These compounds either block glutamate receptors or reduce the amount of glutamate being released by other cells. These compounds may also reduce the amount of glutamate present in the junction between glutamate-releasing nerve cells and glutamate-accepting nerve cells.

For further reading^

  1. Kandel, Eric. Essentials of Neuroscience and Behavior. McGraw-Hill Professional Publishing, 1996.
    This introductory neuroscience textbook contains detailed information on the interplays between neuroscience and behavior. Most of the information presented in this section regarding glutamate and its receptors can be found in Kandel’s book.

-E. Tan, 9-22-01