The lethal mutation in Huntington's disease (HD) is an expanded trinucleotide (CAG) repeat within the huntingtin protein which ultimately causes selective neurodegeneration especially within the striatum and cortex. This proposal examines cellular mechanisms underlying functional alterations in HD. Emerging evidence indicates that dysfunctions of striatal and cortical neurons and circuits occur during the development of the disease phenotype, well before there is significant cell loss. Morphological changes in the striatum are probably primed initially by alterations in the intrinsic functional properties of striatal medium- sized spiny neurons (MSSNs), but ultimately require abnormalities in the corticostriatal glutamatergic inputs for the phenotype to be expressed. Malfunctions of the corticostriatal pathway are complex and there are multiple changes as demonstrated by significant age-related transient and more chronic interactions with the disease state. There also is growing evidence for changes in cortical microcircuits that interact to induce dysfunctions of the corticostriatal pathway. Little is known about the temporal sequence of cellular and circuit alterations, as well as the causes of selective neuronal vulnerability in striatum and cortex. We will use genetically-modified mice to address these important questions. This proposal will examine the functional interactions that occur to make specific neuronal populations more vulnerable to dysfunction and subsequent degeneration in HD. We hypothesize that the most conspicuous cellular alterations leading to dysfunction and pathology in HD result from a combination of cell-cell interactions and are not solely the outcome of cell- autonomous changes. We will test our hypothesis in three specific aims designed to: 1. Determine the electrophysiological properties that make subpopulations of striatal projection neurons and interneurons differentially vulnerable to dysfunction and degeneration in mouse models of HD, 2. Examine the alterations in the balance of excitation and inhibition in the cerebral cortex of mouse models of HD that facilitate and enable abnormalities in the striatum and 3. Examine if widespread expression of mutant huntingtin is necessary to produce differential electrophysiological alterations in identified populations of MSSNs. These studies will provide the basis for novel rational treatments of HD by delineating more restricted targets for drug intervention and also will be relevant for understanding other CAG triplet repeat diseases and neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041574-10
Application #
8084225
Study Section
Special Emphasis Panel (ZRG1-MDCN-L (91))
Program Officer
Sutherland, Margaret L
Project Start
2001-04-01
Project End
2012-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
10
Fiscal Year
2011
Total Cost
$297,125
Indirect Cost
Name
University of California Los Angeles
Department
Psychiatry
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Indersmitten, Tim; Tran, Conny H; Cepeda, Carlos et al. (2015) Altered excitatory and inhibitory inputs to striatal medium-sized spiny neurons and cortical pyramidal neurons in the Q175 mouse model of Huntington's disease. J Neurophysiol 113:2953-66
Valenza, Marta; Chen, Jane Y; Di Paolo, Eleonora et al. (2015) Cholesterol-loaded nanoparticles ameliorate synaptic and cognitive function in Huntington's disease mice. EMBO Mol Med 7:1547-64
Covarrubias-Pinto, Adriana; Moll, Pablo; Solís-Maldonado, Macarena et al. (2015) Beyond the redox imbalance: Oxidative stress contributes to an impaired GLUT3 modulation in Huntington's disease. Free Radic Biol Med 89:1085-96
Holley, Sandra M; Joshi, Prasad R; Parievsky, Anna et al. (2015) Enhanced GABAergic Inputs Contribute to Functional Alterations of Cholinergic Interneurons in the R6/2 Mouse Model of Huntington's Disease. eNeuro 2:
Wang, Nan; Gray, Michelle; Lu, Xiao-Hong et al. (2014) Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington's disease. Nat Med 20:536-41
Botelho, Eliã P; Wang, Elizabeth; Chen, Jane Y et al. (2014) Differential Synaptic and Extrasynaptic Glutamate-Receptor Alterations in Striatal Medium-Sized Spiny Neurons of Aged YAC128 Huntington's Disease Mice. PLoS Curr 6:

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