Fogarty Matthew J, Mu Erica W H, Lavidis Nickolas A, Noakes Peter G, Bellingham Mark C
Faculty of Medicine, School of Biomedical Sciences, University of Queensland, St Lucia, QLD, Australia.
Queensland Brain Institute, University of Queensland, St Lucia, QLD, Australia.
Front Neurosci. 2017 Nov 1;11:609. doi: 10.3389/fnins.2017.00609. eCollection 2017.
Motor neurons (MNs) die in amyotrophic lateral sclerosis (ALS), a clinically heterogeneous neurodegenerative disease of unknown etiology. In human or rodent studies, MN loss is preceded by increased excitability. As increased neuronal excitability correlates with structural changes in dendritic arbors and spines, we have examined longitudinal changes in dendritic structure in vulnerable neuron populations in a mouse model of familial ALS. We used a modified Golgi-Cox staining method to determine the progressive changes in dendritic structure of hippocampal CA1 pyramidal neurons, striatal medium spiny neurons, and resistant (trochlear, IV) or susceptible (hypoglossal, XII; lumbar) MNs from brainstem and spinal cord of mice over-expressing the human SOD1 (SOD1) mutation, in comparison to wild-type (WT) mice, at four postnatal (P) ages of 8-15, 28-35, 65-75, and 120 days. In SOD1 mice, dendritic changes occur at pre-symptomatic ages in both XII and spinal cord lumbar MNs. Spine loss without dendritic changes was present in striatal neurons from disease onset. Spine density increases were present at all ages studied in SOD1 XII MNs. Spine density increased in neonatal lumbar MNs, before decreasing to control levels by P28-35 and was decreased by P120. SOD1 XII MNs and lumbar MNs, but not trochlear MNs showed vacuolization from the same time-points. Trochlear MN dendrites were unchanged. Dendritic structure and spine alterations correlate with the neuro-motor phenotype in ALS and with cognitive and extra-motor symptoms seen in patients. Prominent early changes in dendritic arbors and spines occur in susceptible cranial and spinal cord MNs, but are absent in MNs resistant to loss in ALS.
运动神经元（MNs）在肌萎缩侧索硬化症（ALS）中会死亡，这是一种病因不明的临床异质性神经退行性疾病。在人体或啮齿动物研究中，MNs丧失之前会出现兴奋性增加。由于神经元兴奋性增加与树突分支和棘突的结构变化相关，我们研究了家族性ALS小鼠模型中易损神经元群体树突结构的纵向变化。我们使用改良的高尔基-考克斯染色方法，以确定与野生型（WT）小鼠相比，在出生后8 - 15天、28 - 35天、65 - 75天和120天这四个年龄段，过表达人类超氧化物歧化酶1（SOD1）突变的小鼠的海马CA1锥体神经元、纹状体中等棘状神经元以及脑干和脊髓中抗性（滑车神经，IV）或易感性（舌下神经，XII；腰段）MNs的树突结构的渐进性变化。在SOD1小鼠中，XII和脊髓腰段MNs在症状前年龄段就出现了树突变化。从疾病发作开始，纹状体神经元就出现了无树突变化的棘突丧失。在研究的所有年龄段，SOD1 XII MNs的棘突密度都增加。新生腰段MNs的棘突密度增加，在P28 - 35时降至对照水平，到P120时降低。SOD1 XII MNs和腰段MNs，但滑车神经MNs没有，从相同时间点开始出现空泡化。滑车神经MNs的树突没有变化。树突结构和棘突改变与ALS中的神经运动表型以及患者出现的认知和运动外症状相关。易感性颅神经和脊髓MNs的树突分支和棘突出现显著的早期变化，但在ALS中抗丧失的MNs中不存在这些变化。
