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 #
3R01NS041574-09S2
Application #
8245957
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
2010-06-01
Budget End
2011-05-31
Support Year
9
Fiscal Year
2011
Total Cost
$221,725
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
Reidling, Jack C; Relaño-Ginés, Aroa; Holley, Sandra M et al. (2018) Human Neural Stem Cell Transplantation Rescues Functional Deficits in R6/2 and Q140 Huntington's Disease Mice. Stem Cell Reports 10:58-72
Estrada-Sánchez, Ana María; Castro, Daniel; Portillo-Ortiz, Kenia et al. (2018) Complete but not partial inhibition of glutamate transporters exacerbates cortical excitability in the R6/2 mouse model of Huntington's disease. CNS Neurosci Ther :
Donzis, Elissa J; Holley, Sandra M; Cepeda, Carlos et al. (2018) Neurophysiological Assessment of Huntington's Disease Model Mice. Methods Mol Biol 1780:163-177
Barry, Joshua; Akopian, Garnik; Cepeda, Carlos et al. (2018) Striatal Direct and Indirect Pathway Output Structures Are Differentially Altered in Mouse Models of Huntington's Disease. J Neurosci 38:4678-4694
Parievsky, Anna; Moore, Cindy; Kamdjou, Talia et al. (2017) Differential electrophysiological and morphological alterations of thalamostriatal and corticostriatal projections in the R6/2 mouse model of Huntington's disease. Neurobiol Dis 108:29-44
Lee, Kwang; Holley, Sandra M; Shobe, Justin L et al. (2017) Parvalbumin Interneurons Modulate Striatal Output and Enhance Performance during Associative Learning. Neuron 93:1451-1463.e4
Akopian, Garnik; Barry, Joshua; Cepeda, Carlos et al. (2016) Altered membrane properties and firing patterns of external globus pallidus neurons in the R6/2 mouse model of Huntington's disease. J Neurosci Res 94:1400-1410
Chen, Jane Y; Tran, Conny; Hwang, Lin et al. (2016) Partial Amelioration of Peripheral and Central Symptoms of Huntington's Disease via Modulation of Lipid Metabolism. J Huntingtons Dis 5:65-81
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

Showing the most recent 10 out of 52 publications