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One of the most-studied mechanisms for motor neuron death involves their abnormal stimulation by the amino acid glutamate.

Normally, glutamate acts as a neurotransmitter, carrying messages across synapses throughout the brain and spinal cord. The presence of too much glutamate, however,  kills neurons. This buildup can occur if neurons are overstimulated (known as excitotoxicity) or if cell chemistry goes awry. Normally, it’s prevented by glutamate transporters, molecules embedded in cell membranes that act like “sponges” to remove the neurotransmitter. Glutamate transporters are most plentiful at synapses. Even more exist on the cell membranes of astrocytes, neurons’ central nervous system companion cells.

In the early 1990s, a large study of nearly 400 patients with sporadic ALS showed some 40 percent had increased glutamate levels in cerebrospinal fluid – a byproduct of excitotoxicity. The higher the glutamate levels, scientists found, the more severe the disease.

Packard scientists and others proved glutamate-based excitotoxicity is part of a process leading to motor neuron death in ALS. Glutamate transporters are either inefficient or don’t exist in sufficient supply to prevent glutamate buildup. Up to 80 percent of ALS patients have some abnormality in glutamate transporters, our studies show.

ALS model mice have less than half of the normal glutamate transporters in their spinal cords, a reduction that begins well before symptoms start. Remove glutamate transporters from ALS mice entirely and neurons swiftly die.

Earlier Packard research showed that overexpression of glutamate transporters in mouse models delays onset of symptoms and extends life. More recent Center-assisted studies showed that beta-lactam antibiotics boost transporter numbers, delay disease onset, slow its progression, and prolong life in animal studies.

Excitotoxicity also makes a good therapeutic target and clinical studies are ongoing.

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