We have previously found, based on immunohistochemical studies of postmortem human brain material, that some types of striatal projection neurons are more vulnerable than others in Huntington's disease (HD), with the vulnerable types being lost in greater abundance during the middle stages of adult onset HD. In order to better characterize the differential loss of striatal projection neurons, we propose to use immunohistochemical techniques on postmortem brain specimens to: 1) examine the patterns of loss in the early and late stages of adult onset HD among the types of projection neurons we have already studied; 2)0 examine the pattern of loss at all stages of adult HD for some additional types of striatal projection neurons and 3) examine the early and late stages of juvenile onset HD to explore the possibility that in this form of HD the loss among striatal projection neurons is nondifferential (which is implied by our preliminary data and the clinical features of this form of HD). Image analysis will be used to quantify the extent of loss in comparison to normals for each project system. These data on differential striatal projection neuron vulnerability in HD will provide important information for two lines of studies in rats, both of which relate to the possible role of excitotoxicity in mediating striatal cell death in HD. In the first line of study, we will determine whether striatal projection neurons and interneurons that are less susceptible in HD possess a greater capacity for buffering intracellular calcium (by means of their content of either parvalbumin or calbindin) and can thereby prevent the deleterious cascade of events that ensues from the high calcium influxes that attend an excitotoxic event. In the second line of work we will examine whether exposure of striatal neurons in vivo (by means of intrastriatal injections) or in vitro (by incubation of cultured striatal neurons) to the endogenous NMDA-receptor specific excitotoxin, quinolinic acid (QA), yields the pattern of differential death of striatal projection neurons and interneurons observed in HD. If so, the results would support the possibility that cell death in HD might be mediated by NMDA receptor mediated exictotoxicity. The proposed studies will help clarify the neural bases of the symptoms observed at each stage of HD and shed light on the pathogenetic mechanisms underlying HD, particularly on the hypothesis that NMDA-receptor mediated excitoxicity might underly HD. The information gained from these various studies could have therapeutic or prophylactic implications for HD gene carriers, as well as for other disorders involving excitotoxin-mediated neuronal degeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS028721-01
Application #
3415319
Study Section
Pathology A Study Section (PTHA)
Project Start
1990-07-15
Project End
1994-06-30
Budget Start
1990-07-15
Budget End
1991-06-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Dragatsis, I; Dietrich, P; Ren, H et al. (2018) Effect of early embryonic deletion of huntingtin from pyramidal neurons on the development and long-term survival of neurons in cerebral cortex and striatum. Neurobiol Dis 111:102-117
Reiner, Anton; Deng, Yun-Ping (2018) Disrupted striatal neuron inputs and outputs in Huntington's disease. CNS Neurosci Ther 24:250-280
Deng, Yun-Ping; Reiner, Anton (2016) Cholinergic interneurons in the Q140 knockin mouse model of Huntington's disease: Reductions in dendritic branching and thalamostriatal input. J Comp Neurol 524:3518-3529
Bruce, Laura L; Erichsen, Jonathan T; Reiner, Anton (2016) Neurochemical compartmentalization within the pigeon basal ganglia. J Chem Neuroanat 78:65-86
Reiner, Anton; Shelby, Evan; Wang, Hongbing et al. (2013) Striatal parvalbuminergic neurons are lost in Huntington's disease: implications for dystonia. Mov Disord 28:1691-9
Lei, Wanlong; Deng, Yunping; Liu, Bingbing et al. (2013) Confocal laser scanning microscopy and ultrastructural study of VGLUT2 thalamic input to striatal projection neurons in rats. J Comp Neurol 521:1354-77
Reiner, A; Wang, H B; Del Mar, N et al. (2012) BDNF may play a differential role in the protective effect of the mGluR2/3 agonist LY379268 on striatal projection neurons in R6/2 Huntington's disease mice. Brain Res 1473:161-72
Reiner, A; Lafferty, D C; Wang, H B et al. (2012) The group 2 metabotropic glutamate receptor agonist LY379268 rescues neuronal, neurochemical and motor abnormalities in R6/2 Huntington's disease mice. Neurobiol Dis 47:75-91
Reiner, Anton; Dragatsis, Ioannis; Dietrich, Paula (2011) Genetics and neuropathology of Huntington's disease. Int Rev Neurobiol 98:325-72
Mu, Shuhua; OuYang, Lisi; Liu, Bingbing et al. (2011) Preferential interneuron survival in the transition zone of 3-NP-induced striatal injury in rats. J Neurosci Res 89:744-54

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