Amyotrophic lateral sclerosis (ALS) leads to a loss of specific motor neuron populations in the spinal cord and cortex. Emerging evidence suggests that interneurons may also be affected, but a detailed characterization of interneuron loss and its potential impacts on motor neuron loss and disease progression is lacking. To examine this issue, the fate of V1 inhibitory neurons during ALS was assessed in the ventral spinal cord using the SOD^G93A mouse model. The V1 population makes up ∼30% of all ventral inhibitory neurons, ∼50% of direct inhibitory synaptic contacts onto motor neuron cell bodies, and is thought to play a key role in modulating motor output, in part through recurrent and reciprocal inhibitory circuits. We find that approximately half of V1 inhibitory neurons are lost in SOD^G93A mice at late disease stages, but that this loss is delayed relative to the loss of motor neurons and V2a excitatory neurons. We further identify V1 subpopulations based on transcription factor expression that are differentially susceptible to degeneration in SOD^G93A mice. At an early disease stage, we show that V1 synaptic contacts with motor neuron cell bodies increase, suggesting an upregulation of inhibition before V1 neurons are lost in substantial numbers. These data support a model in which progressive changes in V1 synaptic contacts early in disease, and in select V1 subpopulations at later stages, represent a compensatory upregulation and then deleterious breakdown of specific interneuron circuits within the spinal cord.

肌萎缩性侧索硬化症（ALS）导致脊髓和皮层中特定运动神经元的丢失。新兴证据表明，中间神经元也可能受到影响，但缺乏中间神经元丧失及其对运动神经元丧失和疾病进展的潜在影响的详细表征。为了检查此问题，使用SOD ^G93A小鼠模型评估了腹侧脊髓中ALS期间V1抑制神经元的命运。V1群体约占所有腹侧抑制神经元的30％，约占运动神经元细胞体直接抑制性突触接触的50％，被认为在调节运动输出中起关键作用，部分是通过反复的和相互的抑制性回路。我们发现大约一半的V1抑制神经元在SOD ^G93A中丢失处于疾病晚期的小鼠，但是这种损失相对于运动神经元和V2a兴奋性神经元的损失是延迟的。我们进一步确定基于转录因子表达的V1亚群，它们对SOD ^G93A小鼠的变性易受影响。在疾病的早期阶段，我们显示与运动神经元细胞体的V1突触接触增加，表明在V1神经元大量丢失之前抑制作用的上调。这些数据支持一种模型，其中疾病早期的V1突触接触逐渐发生变化，而在后期的某些V1亚群中，则代表补偿性上调，然后是脊髓内特定中神经元回路的有害破坏。