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Aug 13, 2014

Huntingtin, Potential Target in Huntington’s, Participates in Memory Formation

  • The huntingtin gene’s function in the healthy brain has remained unclear, even while scientists have grown increasingly familiar with the huntingtin gene’s dark side—the mutations that give rise to Huntington’s disease, an inherited disease that causes certain nerve cells in the brain to waste away, causing involuntary movements and, ultimately, emotional disturbance and cognitive impairment.

    Given the devastation wreaked by altered versions of huntingtin, one might be tempted to treat Huntington’s disease by eliminating the huntingtin protein entirely. Yet, if huntingtin serves essential functions, merely getting rid of it altogether could do more harm than good.

    To explore huntingtin’s biological functions, researchers at The Scripps Research Institute and Columbia University decided to focus on wild-type huntingtin. Although wild-type huntingtin had been shown to be important for neuronal functions such as axonal transport, the role of wild-type huntingtin in long-term synaptic plasticity, the researchers realized, had not been investigated in detail.

    The researchers took advantage of a widely used model in genetic studies, the marine snail Aplysia. This snail, it turned out, carries an equivalent of the human huntingtin protein. Just like its human counterpart, the protein in Aplysia is widely expressed in neurons throughout the central nervous system.

    In an article published July 23 in PLOS ONE, in an article entitled, “Huntingtin Is Critical Both Pre- and Postsynaptically for Long-Term Learning-Related Synaptic Plasticity in Aplysia,” the researchers explained their approach: “We chose to study the sensory-to-motor neuron synapse of the Aplysia gill-withdrawal reflex reconstituted in culture in order to examine the function of normal huntingtin in memory storage. In Aplysia, selective manipulation of the presynaptic sensory neurons and postsynaptic motor neurons is readily manageable, and addressing this issue seemed important because long-term memory storage is associated with specific and coordinated pre- and postsynaptic changes.”

    The researchers discovered that the expression of mRNAs of huntingtin is upregulated by repeated applications of serotonin, a modulatory transmitter released during learning in Aplysia. In addition, they found that huntingtin expression levels are critical, not only in presynaptic sensory neurons, but also in the postsynaptic motor neurons for serotonin-induced long-term facilitation at the sensory-to-motor neuron synapse of the Aplysia gill-withdrawal reflex.

    “We found that huntingtin expression levels are necessary for what is known as long-term synaptic plasticity—the ability of the synapses to grow and change—which is critical to the formation of long-term memory,” said TSRI assistant professor Sathyanarayanan V. Puthanveettil, Ph.D., who led the study with Nobel laureate Eric Kandel, M.D., of Columbia University.

    “During the learning, production of the huntingtin mRNAs is increased both in pre- and postsynaptic neurons—that is a new finding,” Dr. Puthanveettil elaborated. “And if you block production of the protein either in pre- or postsynaptic neurons, you block formation of memory.”

    The findings could have implications for the development of future treatments of Huntington’s disease. While the full biological functions of the huntingtin protein are not yet fully understood, the results caution against a therapeutic approach that attempts to eliminate the protein entirely. In the current study, the authors noted, “The same electrophysiological phenotypes observed in our study using the knockdown of the [Aplysia homolog of huntingtin] support the idea that both the gain-of-function from the mutant huntingtin and the loss-of-function from the reduction of wild-type huntingtin may play a role in cognitive deficit in patients with Huntington's disease.”


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