Salamatina, Alina; Yang, Jerry H; Brenner-Morton, Susan; Bikoff, Jay B ; Fang, Linjing; Kintner, Christopher R; Jessell, Thomas M; Sweeney, Lora B.IST Austria
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.
This work was made possible by the generous support of Project ALS. Imaging and related analyses were facilitated by The Waitt Advanced Biophotonics Center Core at the Salk Institute, supported by grants from NIH-NCI CCSG (P30 014195) and NINDS Neuroscience Center (NS072031). The authors would like to additionally thank Drs. Jane Dodd, Robert Brownstone, and Laskaro Zagoraiou for helpful comments on the manuscript. This manuscript is dedicated to Tom Jessell, an inspirational scientist, friend and mentor.
Salamatina A, Yang JH, Brenner-Morton S, et al. Differential loss of spinal interneurons in a mouse model of ALS. Neuroscience. 2020;450:81-95. doi:10.1016/j.neuroscience.2020.08.011
Salamatina, A., Yang, J. H., Brenner-Morton, S., Bikoff, J. B., Fang, L., Kintner, C. R., … Sweeney, L. B. J. (2020). Differential loss of spinal interneurons in a mouse model of ALS. Neuroscience. Elsevier. https://doi.org/10.1016/j.neuroscience.2020.08.011
Salamatina, Alina, Jerry H Yang, Susan Brenner-Morton, Jay B Bikoff, Linjing Fang, Christopher R Kintner, Thomas M Jessell, and Lora Beatrice Jaeger Sweeney. “Differential Loss of Spinal Interneurons in a Mouse Model of ALS.” Neuroscience. Elsevier, 2020. https://doi.org/10.1016/j.neuroscience.2020.08.011.
A. Salamatina et al., “Differential loss of spinal interneurons in a mouse model of ALS,” Neuroscience, vol. 450. Elsevier, pp. 81–95, 2020.
Salamatina A, Yang JH, Brenner-Morton S, Bikoff JB, Fang L, Kintner CR, Jessell TM, Sweeney LBJ. 2020. Differential loss of spinal interneurons in a mouse model of ALS. Neuroscience. 450, 81–95.
Salamatina, Alina, et al. “Differential Loss of Spinal Interneurons in a Mouse Model of ALS.” Neuroscience, vol. 450, Elsevier, 2020, pp. 81–95, doi:10.1016/j.neuroscience.2020.08.011.
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