This is a competing continuation of NS 28721. In this upcoming 5-year project, the applicant will examine the hypothesis that Huntington's disease (HD) is caused by AMPA receptor (AMPAR)-mediated excitotoxicity. He proposes that the HD gene defect leads to selective striatal neuronal death by 1) enrichment in AMPARs and cortical inputs in striatal projection neurons and parvalbuminergic interneurons in HD. 2) A preponderance of GluR2 containing AMPARs in striatal neurons projecting to the internal pallidal segment accounts for their lesser vulnerability in HD and 3) The HD mutation decreases the numbers of group II mGluRs on corticostriatal terminals, thereby increasing cortical activation and excitotoxicity of striatal neurons. The main hypotheses are based on the following observations: a. The HD gene product is widely expressed in the brain, whereas the neurons killed in HD are localized to the striatum b. No cell-type specific proteins that interact with HD proteins are specific to vulnerable striatal neurons. c. The level of huntingtin in a given type of striatal neuron does not seem to correlate with vulnerability. d. There is suggestion that in HD transgenic mice (Bates R6/2), group II mGluRs are downregulated and that sEPSP frequency is increased. e. HD pathology can be reproduced by 3-NP and by quinolinic acid administration f. Neurons that die are rich in cortical input. g. Neurons that die are rich in AMPARs, some of which appear to be more deficient in GluR2 (the GluR2 hypothesis). From these observations, the applicant concludes """"""""the HD mutation may render corticostriatal neurons destructive rather than render striatal neurons vulnerable."""""""" These hypotheses will be tested in 5 Specific Aims:
Aim 1 : Use single cell RT-PCR, immunoprecipitation and LM and EM immunolabeling to characterize the abundance and subunit composition of AMPA receptors present on HD-vulnerable and HD-resistant striatal interneuron and projection neuron types in rats.
Aim 2 : Characterize differences between striatal interneurons and projection neurons in AMPAR mediated synaptic responses to cortical input and in subunit dependent AMPA physiology (Ca permeability, rectification and desensitization) in rats Aim 3: Pharmacologically characterize the role of AMPARs and mGluR2/3-regulatable corticostriatal glutamate release in the selective death of striatal neurons in rats chronically administered 3NP, a model of HD.
Aim 4 : Use in-situ hybridization histochemistry, LM and EM immuno to determine in striatal neurons in monkey and in HD striatum whether the distribution of AMPAR subunits in HD vulnerable and HD resistant striatal neurons is consistent with their hypothesized role in selective neurodegeneration.
Aim 5 : Use in-situ hybridization histochemistry, LM and EM immuno to determine in a transgenic rat model of HD and in human HD specimens whether or not the HD mutation decreases mGluR2/3 in corticostriatal neurons and their intrastriatal terminals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS028721-11
Application #
6393459
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Oliver, Eugene J
Project Start
1990-07-15
Project End
2005-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
11
Fiscal Year
2001
Total Cost
$319,500
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Anatomy/Cell Biology
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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