Location, location, location

A drug that inhibits excitatory activity in the brain can either improve or worsen the progression of Huntington's disease (HD) depending on where on neurons its targets are located. The finding, published online this week in Nature Medicine, may offer a new therapeutic approach towards Huntington's disease.

HD is a condition characterized by neuronal death in the brain region termed striatum ― which plays an important role in planning and executing movement. The disease is caused by mutations in the gene encoding the protein huntingtin, and results in the formation of huntingtin aggregates in the affected neurons; these aggregates may have a protective role early in the disease.

Stuart Lipton and his colleagues looked at the link between HD, the excessive excitatory brain activity observed, and the huntingtin aggregate formation. Using mice that express mutant forms of huntingtin, the team tested the effect on neurons of different doses of the drug memantine on neurons. This drug inhibits the NMDA receptors in the brain, which are a key subtype of the main excitatory receptors in the brain.

They found that a low dose of memantine blocked NMDA receptors found outside of the synapse ― and therefore reduced the severity of HD in the mice ― such as neuronal death and behavioral deficits. By contrast, the scientists found, that a high dose of memantine that blocked NMDA receptors found on both the synapse and outside of the synapse decreased the number of huntingtin clumps and in fact worsened the disease.

Lipton and colleagues also established that the location of NMDA receptors on the neuron determines whether their activation will lead to aggregate formation and neuronal survival or to aggregate dissolution and neuronal death. Importantly, memantine is already used in the clinic to treat patients with Alzheimer's disease, therefore tinkering with its dose to only target NMDA receptors in certain cellular locations may help with Huntington's treatment.