Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis
Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis
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DOI：
10.1002/brb3.104
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发表时间：
2013-03-01
影响因子：
3.1
通讯作者：
Navarro, Xavier
中科院分区：
文献类型：
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作者：
Casas, Caty;Herrando-Grabulosa, Mireia;Navarro, Xavier
散发性和常见的肌萎缩侧索硬化症（ALS）患者的脊髓运动神经元（MNs）的胆碱能活性低于健康人，这表明胆碱能活性降低可能发生在MN死亡之前。为了揭示胆碱能功能受损的方式和时间，我们通过共聚焦免疫组织化学分析了SOD1(G93A) ALS小鼠模型早期症状前阶段胆碱乙酰转移酶（ChAT）的时空表达。分析显示，30日龄SOD1（G93A）小鼠的体细胞和突触前扣与MNs相连接的ChAT含量早期减少（76%），腰椎胆碱能中间神经元的ChAT含量早期减少。胆碱能突触剥离与周围大量主要组织相容性复合体II （MHC-II）阳性小胶质细胞的存在、核Tdp-43的积累以及MNs内轻度氧化应激的出现同时发生。此外，神经细胞MHC-I表达缺失，这是轴切后突触剥离平衡所必需的。这些事件发生在选择性地提高诸如ATF3之类的去神经标志之前。与此同时，突触后胆碱能相关结构的改变也随着突触后池中Ca2+缓冲伴侣sigma-1受体的缺失而被揭示。到2月龄时，ChAT似乎在MNs的胞体中积累，因此对Renshaw中间神经元的影响急剧减弱。综上所述，脊髓局部电路胆碱能功能障碍可能是ALS发病的最早事件之一。
Sporadic and familiar amyotrophic lateral sclerosis (ALS) cases presented lower cholinergic activity than in healthy individuals in their still preserved spinal motoneurons (MNs) suggesting that cholinergic reduction might occur before MN death. To unravel how and when cholinergic function is compromised, we have analyzed the spatiotemporal expression of choline acetyltransferase (ChAT) from early presymptomatic stages of the SOD1(G93A) ALS mouse model by confocal immunohistochemistry. The analysis showed an early reduction in ChAT content in soma and presynaptic boutons apposed onto MNs (to 76%) as well as in cholinergic interneurons in the lumbar spinal cord of the 30-day-old SOD1(G93A) mice. Cholinergic synaptic stripping occurred simultaneously to the presence of abundant surrounding major histocompatibility complex II (MHC-II)-positive microglia and the accumulation of nuclear Tdp-43 and the appearance of mild oxidative stress within MNs. Besides, there was a loss of neuronal MHC-I expression, which is necessary for balanced synaptic stripping after axotomy. These events occurred before the selective raise of markers of denervation such as ATF3. By the same time, alterations in postsynaptic cholinergic- related structures were also revealed with a loss of the presence of sigma-1 receptor, a Ca2+ buffering chaperone in the postsynaptic cisternae. By 2 months of age, ChAT seemed to accumulate in the soma of MNs, and thus efferences toward Renshaw interneurons were drastically diminished. In conclusion, cholinergic dysfunction in the local circuitry of the spinal cord may be one of the earliest events in ALS etiopathogenesis.