This proposal will examine cellular mechanisms underlying the dysfunctions detected in Huntington's disease (HD) using four different murine models. The lethal mutation in HD produces an expanded trinucleotide (GAG) repeat within the protein huntingtin. It causes selective neurodegeneration especially in the striatum and cortex, by an unidentified mechanism. Each of the HD models we will examine exhibits a different phenotype produced by unique transgene constructs or 'knocked-in"""""""" GAG repeat lengths. By evaluating multiple models we will be able to examine the dysfunctions in more detail and understand the specificity and sequence of physiological changes common to HD and the models. Based on our preliminary studies, we have uncovered several common cellular deficits in two models. These are enhanced responsiveness of N-methyl-D-aspartate (NMDA) receptors in the striatum associated with increased Ca2+ flux, a marked decrease in K+ conductances and a change in the corticostriatal synaptic response. A third model also displays the enhanced response to NMDA. Some of these changes potentially predispose striatal medium-sized spiny neurons to excitotoxic damage. Using a physiological approach, we will examine four hypotheses concerning the cellular mechanisms of dysfunction in HD: 1) alterations in ionotropic glutamate receptor function and changes in evoked and spontaneous excitatory synaptic inputs to striatal neurons 2) alterations in metabotropic glutamate and dopaminergic receptor modulation of ionotropic glutamate receptor function, 3) alterations in K+ conductances and 4) alterations in Ca2+ conductances. The precise onset of changes will be investigated in relationship to the expression of behavioral deficits by using animals that are presymptomatic or after development of overt motor signs. We will examine striatal and corticostriatal neurons, visualized in the slice preparation or acutely dissociated cells, to characterize basic functions by current- and voltage-clamp analyses. Because HD destroys so many different capabilities - intellectual, physical and emotional - the insights gained from this research elucidating the cellular malfunctions in HD are relevant to understanding other GAG repeat disorders and neurological diseases associated with protein aggregate pathologies like Alzheimer's and Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041574-03
Application #
6745958
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Oliver, Eugene J
Project Start
2002-06-01
Project End
2007-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
3
Fiscal Year
2004
Total Cost
$325,969
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
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