Progressive Changes in Synaptic Inputs to Motoneurons in Adult Sacral Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis
Progressive Changes in Synaptic Inputs to Motoneurons in Adult Sacral Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis
复制标题
DOI：
10.1523/jneurosci.0574-09.2009
复制
发表时间：
2009-12-02
影响因子：
5.3
通讯作者：
Heckman, C. J.
中科院分区：
文献类型：
--
作者：
Jiang, Mingchen;Schuster, Jenna E.;Heckman, C. J.
肌萎缩侧索硬化症（ALS）是一种以运动神经元进行性变性为特征的疾病。一个潜在的机制是兴奋性毒性。我们研究了脊髓神经元的行为，在体外制备的骶髓从G93A SOD1小鼠模型的ALS。在症状前[大约出生后第50天（类似于P50）]、疾病早期（类似于P90）和晚期（>P120）阶段进行测量。短潜伏期反射（SRs）在腹根，推测单突触，诱发电刺激的背根。通过测量由远端腹根的逆向刺激诱发的复合动作电位[总运动活动（TMA）]来评价能够响应这种激活的运动神经元的分数。在突变SOD 1（mSOD 1）小鼠，SR和TMA随着年龄的增长而下降，与非转基因同窝仔相比，排除SR作为兴奋性毒性增加的来源。使用通过浴施用抑制性神经递质（甘氨酸，GABA（A））的阻断剂和谷氨酸受体（尤其是NMDA受体）的激动剂产生的同步腹根爆发来评估脊髓中间神经元活性。症状发作后，mSOD 1小鼠的制剂中有更高百分比表现出爆发，这些爆发表现出更多的子爆发和更混乱的模式。在mSOD1小鼠明确的肌肉震颤，前根表现出自发同步爆发，这是高度敏感的NMDA受体的封锁。这些数据表明，虽然短潜伏期的感觉输入不增加症状的发展，中间神经元活动增加，并可能有助于兴奋性毒性。
Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motoneurons. One potential mechanism is excitotoxicity. We studied the behaviors of spinal neurons using an in vitro preparation of the sacral cord from the G93A SOD1 mouse model of ALS. Measurements were conducted at presymptomatic [approximately postnatal day 50 (similar to P50)], early (similar to P90), and late (>P120) stages of the disease. Short-latency reflexes (SRs) in ventral roots, presumably monosynaptic, were evoked by electrical stimulation of a dorsal root. The fraction of motoneurons capable of responding to this activation was evaluated by measuring the compound action potential [total motor activity (TMA)] evoked by antidromic stimulation of the distal ventral root. In mutant SOD1 (mSOD1) mice, both the SR and the TMA decreased with age compared with nontransgenic littermates, ruling out the SR as a source of increasing excitotoxicity. Spinal interneuron activity was assessed using the synchronized ventral root bursts generated by both bath application of blockers of inhibitory neurotransmitters (glycine, GABA(A)) and agonists of glutamate receptors (especially NMDA receptors). After symptom onset, a higher percentage of preparations from mSOD1 mice exhibited bursting, and these bursts exhibited more sub-bursts and a more disorganized pattern. In mSOD1 mice with clear muscle tremor, the ventral roots exhibited spontaneous synchronized bursts, which were highly sensitive to the blockade of NMDA receptors. These data suggest that although short-latency sensory input does not increase as symptoms develop, interneuron activity does increase and may contribute to excitotoxicity.