The proposed work is relevant to striatal neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), and HIV-associated neurocognitive disorder (HAND), where neuroinflammation and abnormal motor behaviors coincide with disease progression. Voluntary movements are results of precise dopaminergic and glutamatergic convergence on striatal medium spiny neurons (MSNs). Striatal neurodegenerative disorders clinically manifest when there is severe dysregulation of MSN firing. Although these striatal neurodegenerative disorders have differing pathogeneses, they all share increased neuroinflammation and D2 MSN dysfunction. Interestingly, both neuroinflammation and D2 MSN dysfunction occurs early in these diseases, and sometimes before there is detectable neuronal loss. Therefore, elucidating early mechanisms of cellular dysfunction is important to discover novel druggable targets. The preliminary data presented in the proposal suggests differential sensitivity of D2 MSNs to inflammatory conditions, which is an exciting and novel finding. Furthermore, preliminary data also suggest a role for calcium- permeable kainate receptors on D2 MSNs, which will be further explored in inflammatory conditions. Kainate receptor function in the striatum is still poorly understood, thus this work wil at a minimum further our understanding of their role in the striatum. Calcium imaging, electrophysiology, and biochemistry, will be used to assess calcium-permeable AMPAR and kainate receptor distributions in D1 and D2 MSNs. The current proposal provides a new perspective in determining how neuroinflammation can contribute to calcium- permeable AMPA and kainate receptor alterations in MSNs, which will increase our understanding of early D2 MSN dysfunction.
The current proposal provides a novel perspective in determining how neuroinflammation can contribute to calcium-permeable AMPA and kainate receptor alterations in striatal medium spiny neurons (MSNs). This work will address differential changes in calcium-permeable AMPA and kainate receptors in dopamine-2 expressing MSNs, which is relevant to Huntington's disease, Parkinson's disease, and HIV-associated neurocognitive disorder. Although these striatal neurodegenerative disorders have different pathogeneses, they all share increased neuroinflammation and D2 MSN dysfunction. Interestingly, both neuroinflammation and D2 MSN dysfunction occurs early in these diseases, and sometimes before there is detectable neuronal loss. Therefore, elucidating early mechanisms of cellular dysfunction is important to provide novel druggable targets. Lastly, the preliminary data presented in the proposal suggests differential sensitivity of D2 MSNs to inflammatory conditions, which is an exciting and novel finding.
| Winland, Carissa D; Welsh, Nora; Sepulveda-Rodriguez, Alberto et al. (2017) Inflammation alters AMPA-stimulated calcium responses in dorsal striatal D2 but not D1 spiny projection neurons. Eur J Neurosci 46:2519-2533 |
