. 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.

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  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.

  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.

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  1. Striatal Networks Go Haywire in Early Huntington’s Disease