Differential Electrophysiological Changes in Striatal Output Neurons in Huntington's Disease

被引:105
作者
Andre, Veronique M. [1 ]
Cepeda, Carlos [1 ]
Fisher, Yvette E. [1 ]
Huynh, My [1 ]
Bardakjian, Nora [1 ]
Singh, Sumedha [1 ]
Yang, X. William [1 ,2 ]
Levine, Michael S. [1 ]
机构
[1] Univ Calif Los Angeles, David Geffen Sch Med, Intellectual & Dev Disabil Res Ctr, Semel Inst,Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, David Geffen Sch Med, Ctr Neurobehav Genet, Los Angeles, CA 90095 USA
基金
美国国家卫生研究院;
关键词
YAC128 MOUSE MODEL; SPINY NEURONS; CORTICOSTRIATAL PATHWAY; PROJECTION NEURONS; MUTANT HUNTINGTIN; PREFERENTIAL LOSS; MOTOR DEFICITS; BASAL GANGLIA; DOPAMINE; EXPRESSION;
D O I
10.1523/JNEUROSCI.3539-10.2011
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
There is considerable evidence that alterations in striatal medium-sized spiny neurons (MSSNs) giving rise to the direct (D1 receptor-expressing) and indirect (D2 receptor-expressing) pathways differentially contribute to the phenotype of Huntington's disease (HD). To determine how each subpopulation of MSSN is functionally affected, we examined spontaneous excitatory postsynaptic currents (sEPSCs) and dopamine (DA) modulation in two HD mouse models, the YAC128 and the BACHD (a bacterial-artificial chromosome). These mice also expressed enhanced green fluorescent protein (EGFP) under the control of the promoter for either DA D1 or D2 receptors to identify neurons. In early symptomatic YAC128 and BACHD mice, glutamate transmission was increased in both D1 and D2 MSSNs, but in different ways. D1 cells displayed increased sEPSC frequencies and decreased paired-pulse ratios (PPRs) while D2 cells displayed larger evoked glutamate currents but no change in sEPSC frequencies or PPRs. D1 receptor modulation of sEPSCs was absent in D1-YAC128 cells at the early symptomatic stage but was restored by treating the slices with tetrabenazine. In contrast, in fully symptomatic YAC128 mice, glutamate transmission was decreased specifically in D1 cells, and D1 receptor modulation was normal in D1-YAC128 cells. Behaviorally, early symptomatic mice showed increased stereotypies that were decreased by tetrabenazine treatment. Together, these studies support differential imbalances in glutamate and DA transmission in direct and indirect pathway MSSNs. Stereotypic behavior at an early stage could be explained by increased glutamate activity and DA tone in direct pathway neurons, whereas hypokinesia at later stages could result from reduced input onto these neurons.
引用
收藏
页码:1170 / 1182
页数:13
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