Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder resulting in prominent motor and cognitive dysfunction. Although degneration of the striatum and basal ganglia structures is the pathological hallmark, prominent structural and functional changes of the cerebral cortex also affect HD patients. In fact, disruption of cognitive processes often occur prior to motor symptoms and some disruptions, such as attention and working memory impairments, can be attributed to dysfunction of the prefrontal cortex (PFC). Research from genetic mouse models of HD have demonstrated that the phenotype is only expressed when cortical neuropathology is detectable, indicating the cortex plays a prominent role in the development of symptoms. We have recently reported multiple alterations in the firing properties of neurons recorded in the PFC of behaving R6/2 mice, the niost popular genetic HD mouse model. Relative to wild-type (WT), individual neurons in R6/2 mice have a higher firing rate and less burst activity. Pairs of simultaneously recorded neurons, furthermore, have a significant reduction in synchrous firing in R6/2 mice. The overall goal of the work in this proposal aims to determine if disrupted PFC processing results in behavioral impairments and to determine if altered P,FC activity can be treated pharmacologically. Behaviorally, WT and R6/2 mice will be trained in extinction of conditioned fear, a PFC relevant task, while neural activity is recorded. We hypothesize that R6/2 mice will exhibit disrupted extinction of conditioned fear and PFC neurons will respond abnormally during training. The second aspect of this proposal aims to test the hypothesis that adminstration of selective metabotropic glutmate receptor 2/3 (mGluR2/3) agonists will reverse or prevent alterations to PFC processing in R6/2 mice. Previous research has shown that mGluR2/3 agonists are able to restore firing rate and bursting abnormalities in the PFC in other disease models and that chronic administration of these compounds improve the phenotype in R6/2 mice. Thus, R6/2 mice will be treated acutely or chronically with LY379268, an mGluR2/3 agonist, and PFC activity will be recorded. We hypothesize that the firing rate, bursting properties, and the amount of neural synchrony will normalize and be similar to WT animals. Overall, the work in this proposal has relevance for the cognitive symptoms experienced by HD patients that are attributable to PFC dysfunction. Specifically, this work could result in a high throughput behavioral test to screen potential therapeutic strategies. In addition, the research in this proposal will determine the therapeutic potential of mGluR2/3 agonists in the treatment of PFC dysfunction in HD.
| Wilber, A A; Walker, A G; Southwood, C J et al. (2011) Chronic stress alters neural activity in medial prefrontal cortex during retrieval of extinction. Neuroscience 174:115-31 |
| Walker, Adam G; Ummel, Jason R; Rebec, George V (2011) Reduced expression of conditioned fear in the R6/2 mouse model of Huntington's disease is related to abnormal activity in prelimbic cortex. Neurobiol Dis 43:379-87 |
