The brain is complex and heterogeneous. Even though numerous independent studies indicate cortical hyperexcitability as a potential contributor to amyotrophic lateral sclerosis (ALS) pathology, the mechanisms that are responsible for upper motor neuron (UMN) vulnerability remain elusive. To reveal the electrophysiological determinants of corticospinal motor neuron (CSMN, a.k.a UMN in mice) vulnerability, we investigated the motor cortex of hSOD1^G93A mice at P30 (postnatal day 30), a presymptomatic time point. Glutamate uncaging by laser scanning photostimulation (LSPS) revealed altered dynamics especially within the inhibitory circuitry and more specifically in L2/3 of the motor cortex, whereas the excitatory microcircuits were unchanged. Observed microcircuitry changes were specific to CSMN in the motor column. Electrophysiological evaluation of the intrinsic properties in response to the microcircuit changes, as well as the exon microarray expression profiles of CSMN isolated from hSOD1^G93A and healthy mice at P30, revealed the presence of a very dynamic set of events, ultimately directed to establish, maintain and retain the balance at this early stage. Also, the expression profile of key voltage-gated potassium and sodium channel subunits as well as of the inhibitory GABA receptor subunits and modulatory proteins began to suggest the challenges CSMN face at this early age. Since neurodegeneration is initiated when neurons can no longer maintain balance, the complex cellular events that occur at this critical time point help reveal how CSMN try to cope with the challenges of disease manifestation. This information is critically important for the proper modulation of UMNs and for developing effective treatment strategies.

大脑是复杂且异质的。尽管大量独立研究表明皮质过度兴奋是肌萎缩性侧索硬化症（ALS）病理的潜在原因，但导致上运动神经元（UMN）脆弱的机制仍然难以捉摸。为了揭示皮质脊髓运动神经元（CSMN，又名小鼠UMN）脆弱性的电生理决定因素，我们研究了hSOD1 ^G93A的运动皮质P30（出生后第30天），即症状发生前的时间点。激光扫描光刺激（LSPS）释放的谷氨酸盐揭示动力学变化，尤其是在抑制性电路内，更具体地讲在运动皮层的L2 / 3内，而兴奋性微电路没有变化。观察到的微电路变化特定于电机列中的CSMN。电生理评估响应微电路变化的固有特性，以及从hSOD1 ^G93A分离的CSMN的外显子微阵列表达谱和健康的小鼠在P30时发现存在一系列非常动态的事件，这些事件最终旨在在此早期阶段建立，维持和保持平衡。同样，关键的电压门控钾和钠通道亚基以及抑制性GABA受体亚基和调节蛋白的表达谱也开始提示CSMN在这个早期阶段所面临的挑战。由于神经变性是在神经元不再保持平衡时开始的，因此在这个关键时间点发生的复杂细胞事件有助于揭示CSMN如何应对疾病表现的挑战。该信息对于正确调制UMN和开发有效的治疗策略至关重要。