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
- Johnson MA, Rajan V, Miller CE, Wightman RM. Dopamine release is severely compromised in the R6/2 mouse model of Huntington's disease. J Neurochem. 2006 May;97(3):737-46. PubMed.
- Cayzac S, Delcasso S, Paz V, Jeantet Y, Cho YH. 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.