Before they lose control of their muscles, many Huntington’s patients begin losing their faculties—and scientists are beginning to figure out what brings on this mental decline. In the May 16 Proceedings of the National Academy of Sciences USA online, Yoon Cho and colleagues at the University of Bordeaux, France, report neural network abnormalities in pre-motor HD transgenic mice struggling with a memory task. Echoing a theme in Alzheimer’s and other neurodegenerative disorders, the findings confirm that neuronal dysfunction can develop in advance of overt HD symptoms, shifting the therapeutic window toward earlier stages of disease.

To probe this pivotal pre-motor period, first author Sebastien Cayzac and colleagues analyzed neuronal function in R6/1 mice, which live longer and develop disease more slowly than the more commonly used strain (R6/2). The researchers implanted electrodes into the striatum or cortex, placed the animals into an experimental chamber, and recorded neuronal activity as the rodents learned to poke their nose through small holes to earn drops of sweet milk. “The mouse learns by trial and error what to do to get the milk. It has to select the proper behavior and eliminate irrelevant ones,” Cho said. “For that, the striatum is necessary.”

Not only did pre-symptomatic HD mice do poorly in the procedural learning task, compared to wild-type controls, but they also recruited far fewer projection cells, the striatal population most vulnerable in HD. Nevertheless, “we think those cells are alive because there is no cell loss in the R6/1 model,” Cho said. “The cells are there, but they don’t function properly.”

Even more striking was the strange rhythmic firing of striatal and cortical neurons in task-engaged HD mice. “The neuronal networks formed by these cells oscillated at high frequencies in the γ range, a network behavior not seen in normal mice,” commented Kerry Murphy of the Open University in Milton Keynes, U.K., in an e-mail to ARF (see full comment below). The Bordeaux researchers propose that these abnormal firing patterns may be tied with high dopamine levels in the R6/1 mice. However, “the literature suggests the converse may be the case (see Johnson et al., 2006), and thus, we have a conundrum,” Murphy wrote, noting he will soon submit a paper that partially clarifies this dilemma.

On the whole, George Rebec of Indiana University Bloomington finds the results interesting because they provide strong support for the hypothesis that striatal and cortical neurons start malfunctioning long before they die. “This has important implications for treatment because it suggests that simply preventing neurons from dying is not sufficient to treat Huntington’s disease,” Rebec wrote in an e-mail to ARF. Therapies should focus instead on what makes the cells dysfunctional, he noted (see full comment below). In fact, as is the case in Alzheimer’s and Parkinson’s diseases, ongoing observational studies of pre-manifest HD mutation carriers are laying the groundwork for therapeutic intervention early on.

Along these lines, Cho wonders whether stemming the abnormal striatal/cortical firing patterns could hold promise as a therapeutic strategy for HD. In Parkinson’s disease, substantia nigra cells fire abnormally—oscillating at frequencies in the β range—and drugs that reduce the deviant firing also relieve motor symptoms. “We imagine it might be the same story for γ oscillation in HD,” Cho said.

Meanwhile, a study published earlier this month in Neuron sheds insight into HD, and other polyglutamine diseases, at the level of transcription. Antisense transcripts might be major source of the CAG nucleotide repeats that drive some of these disorders. (see ARF related news story).—Esther Landhuis


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Comments on News and Primary Papers

  1. These results are very interesting because they provide strong support for the hypothesis that there is striatal/cortical neuronal dysfunction that occurs long before neuron death in Huntington’s disease. This has important implications for treatment because it suggests that simply rescuing neurons (preventing them from dying) is not sufficient to treat HD. Neurons are dysfunctional long before they are dead. As my group and others have suggested, the therapeutic focus should be on what is making these neurons dysfunctional. The results also support growing evidence of a neural circuit problem (i.e., how neurons interact with each other) in Huntington’s and perhaps other neurodegenerative diseases. This means that, even though some neuron types and some brain regions show more pathology than others, neural systems beyond these regions are also likely to be affected.

    View all comments by George V. Rebec
  2. A Dopaminergic Conundrum
    There is a growing awareness in the Huntington’s disease (HD) research community that a better understanding of the disease during that critical period prior to the manifestation of overt symptoms might provide much-needed insight for the development of more effective therapies. This fascinating paper from the Bordeaux group in France describes a series of experiments where a learning test, coupled to a means to measure brain activity, has been used to examine the behavior of neuronal networks during the acquisition and performance of a memory task. Crucially, they used a transgenic mouse model of HD that develops the disease at a slower rate, enabling them to conduct their experiments during that key period prior to the development of overt disease symptoms. Their experiments reveal that during learning in pre-symptomatic mice, fewer neurons are recruited in the striatum, a brain region vulnerable in HD, and as a consequence, these mice do not perform as well as normal mice in the learning task. However, the truly remarkable finding of this study is that, during the performance of the task, neurons in both the striatum and cortex exhibit an unusual pattern of activity. The neuronal networks formed by these cells oscillate at a high frequency in the γ range, a network behavior not seen in normal mice. The Bordeaux group suggest that this unusual pattern of firing may be caused by increased levels of dopamine, a chemical transmitter in the brain that has profound effects on the way neurons interact with each other. The sting in the tail, however, is that the literature suggests the converse may be the case, and thus, we have a conundrum. Whilst we still have some way to go from the mouse trap to the clinic, the discovery of γ oscillations in the early stages of the disease in these mice provides the bait, which when digested, may offer a means to unravel the conundrum and reveal a target for therapeutic intervention.

    View all comments by Kerry Murphy


News Citations

  1. Making (Anti)sense of Rare Huntington’s Variant

Paper Citations

  1. . Dopamine release is severely compromised in the R6/2 mouse model of Huntington's disease. J Neurochem. 2006 May;97(3):737-46. PubMed.

Further Reading

Primary Papers

  1. . Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease. Proc Natl Acad Sci U S A. 2011 May 31;108(22):9280-5. PubMed.