Resistance to NMDA toxicity correlates with appearance of nuclear inclusions, behavioural deficits and changes in calcium homeostasis in mice transgenic for exon 1 of the huntington gene

被引:115
作者
Hansson, O
Guatteo, E
Mercuri, NB
Bernardi, G
Li, XJ
Castilho, RF
Brundin, P
机构
[1] Lund Univ, Wallenberg Neurosci Ctr, Sect Neuronal Survival, S-22184 Lund, Sweden
[2] Fdn Santa Lucia, IRCCS, Rome, Italy
[3] Univ Roma Tor Vergata, Neurol Clin, Rome, Italy
[4] Emory Univ, Sch Med, Dept Genet, Atlanta, GA USA
[5] Univ Estadual Campinas, Sch Med Sci, Dept Clin Pathol, Campinas, Brazil
关键词
calcium; cell death; excitotoxicity; Huntington's disease; NMDA receptor; striatum; tolerance; transgenic mouse;
D O I
10.1046/j.0953-816x.2001.01767.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Transgenic Huntington's disease (HD) mice, expressing exon 1 of the human HD gene (lines R6/1 and R6/2), are totally resistant to striatal lesions caused by the NMDA receptor agonist quinolinic acid (QA). Here we show that this resistance develops gradually over time in both R6/1 and R6/2 mice, and that it occurred earlier in R6/2 (CAG-155) than in R6/1 (CAG-115) mice. The development of the resistance coincided with the appearance of nuclear inclusions and with the onset of motor deficits. In the HD mice, hippocampal neurons were also resistant to QA, especially in the CA1 region. Importantly, there was no change in susceptibility to QA in transgenic mice with a normal CAG repeat (CAG-18). R6/1 mice were also resistant to NMDA-, but not to AMPA-induced striatal damage. Interestingly, QA-induced current and calcium influx in striatal R6/2 neurons were not decreased. However, R6/2 neurons had a better capacity to handle cytoplasmic calcium ([Ca2+](c)) overload following OA and could avoid [Ca2+](c) deregulation and cell lysis. In addition, basal [Ca2+](c) levels were increased five-fold in striatal R6/2 neurons. This might cause an adaptation of R6 neurons to excitotoxic stress resulting in an up-regulation of defense mechanisms, including an increased capacity to handle [Ca2+](c) overload. However, the increased level of basal [Ca2+](c) in the HD mice might also disturb intracellular signalling in striatal neurons and thereby cause neuronal dysfunction and behavioural deficits.
引用
收藏
页码:1492 / 1504
页数:13
相关论文
共 91 条
[21]  
Coggeshall RE, 1996, J COMP NEUROL, V364, P6, DOI 10.1002/(SICI)1096-9861(19960101)364:1<6::AID-CNE2>3.0.CO
[22]  
2-9
[23]   THE CALCIUM RESPONSE TO THE EXCITOTOXIN KAINATE IS AMPLIFIED BY SUBSEQUENT REDUCTION OF EXTRACELLULAR-SODIUM [J].
COURTNEY, MJ ;
ENKVIST, MOK ;
AKERMAN, KEO .
NEUROSCIENCE, 1995, 68 (04) :1051-1057
[24]   Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice [J].
Cummings, CJ ;
Reinstein, E ;
Sun, YL ;
Antalffy, B ;
Jiang, YH ;
Ciechanover, A ;
Orr, HT ;
Beaudet, AL ;
Zoghbi, HY .
NEURON, 1999, 24 (04) :879-892
[25]   Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation [J].
Davies, SW ;
Turmaine, M ;
Cozens, BA ;
DiFiglia, M ;
Sharp, AH ;
Ross, CA ;
Scherzinger, E ;
Wanker, EE ;
Mangiarini, L ;
Bates, GP .
CELL, 1997, 90 (03) :537-548
[26]   Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain [J].
DiFiglia, M ;
Sapp, E ;
Chase, KO ;
Davies, SW ;
Bates, GP ;
Vonsattel, JP ;
Aronin, N .
SCIENCE, 1997, 277 (5334) :1990-1993
[27]   EXCITOTOXIC INJURY OF THE NEOSTRIATUM - A MODEL FOR HUNTINGTONS-DISEASE [J].
DIFIGLIA, M .
TRENDS IN NEUROSCIENCES, 1990, 13 (07) :286-289
[28]  
DiIorio P, 1996, J NEUROCHEM, V67, P302
[29]   Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease [J].
Ferrante, RJ ;
Andreassen, OA ;
Jenkins, BG ;
Dedeoglu, A ;
Kuemmerle, S ;
Kubilus, JK ;
Kaddurah-Daouk, R ;
Hersch, SM ;
Beal, MF .
JOURNAL OF NEUROSCIENCE, 2000, 20 (12) :4389-4397
[30]   AN IMMUNOHISTOCHEMICAL INVESTIGATION OF THE HUMAN NEOSTRIATUM IN HUNTINGTONS-DISEASE [J].
GOTO, S ;
HIRANO, A ;
ROJASCORONA, RR .
ANNALS OF NEUROLOGY, 1989, 25 (03) :298-304