Differential Loss of Spinal Interneurons in a Mouse Model of ALS

• Published in: Neuroscience 2020-12, Vol.450, p.81-95
• Main Authors: Salamatina, Alina, Yang, Jerry H., Brenner-Morton, Susan, Bikoff, Jay B., Fang, Linjing, Kintner, Christopher R., Jessell, Thomas M., Sweeney, Lora B.
• Format: Article
• Language: English
• Subjects: amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Animals; differential susceptibility; Disease Models, Animal; inhibitory interneuron; Interneurons; Mice; Mice, Transgenic; motor neuron; Motor Neurons; Spinal Cord; Superoxide Dismutase - genetics; V1 interneuron
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2020.08.011

•Loss of V1 inhibitory neurons in the SODG93A mouse model of ALS.•V1 loss occurs after motor and excitatory V2a neuron loss during disease progression.•Developmental markers of V1 inhibitory neuron subpopulations are maintained to adult stages.•Identification of ALS-susceptible and ALS-resistant V1 inhibitory subpopulations at late stages of disease.•V1 to motor neuron synaptic contacts increase at early ALS stages. 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 SODG93A 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 SODG93A 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 SODG93A 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.