Spinal inhibitory neurons degenerate before motor neurons and excitatory neurons in a mouse model of ALS

Roser Montañana-Rosell, Raghavendra Selvan, Pablo Hernández-Varas, Jan M. Kaminski, Simrandeep Kaur Sidhu, Dana B. Ahlmark, Ole Kiehn, Ilary Allodi

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Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of somatic motor neurons. A major focus has been directed to motor neuron intrinsic properties as a cause for degeneration, while less attention has been given to the contribution of spinal interneurons. In the present work, we applied multiplexing detection of transcripts and machine learning-based image analysis to investigate the fate of multiple spinal interneuron populations during ALS progression in the SOD1G93A mouse model. The analysis showed that spinal inhibitory interneurons are affected early in the disease, before motor neuron death, and are characterized by a slow progressive degeneration, while excitatory interneurons are affected later with a steep progression. Moreover, we report differential vulnerability within inhibitory and excitatory subpopulations. Our study reveals a strong interneuron involvement in ALS development with interneuron specific degeneration. These observations point to differential involvement of diverse spinal neuronal circuits that eventually may be determining motor neuron degeneration.

Original languageEnglish
Article numbereadk3229
JournalScience Advances
Volume10
Issue number22
Number of pages18
ISSN2375-2548
DOIs
Publication statusPublished - 2024

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