open access publication

Article, 2024

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

Science Advances, ISSN 2375-2548, Volume 10, 22, Page eadk3229, 10.1126/sciadv.adk3229

Contributors

Montañana-Rosell, Roser 0000-0003-4268-4765 [1] Selvan, Raghavendra 0000-0003-4302-0207 [1] Hernández-Varas, Pablo 0000-0001-8664-9203 [1] Kaminski, Jan M [1] Sidhu, Simrandeep Kaur 0000-0002-3107-5502 [1] Ahlmark, Dana B [1] Kiehn, Ole 0000-0002-5954-469X (Corresponding author) [1] Allodi, Ilary 0000-0003-4361-163X (Corresponding author) [1] [2]

Affiliations

  1. [1] University of Copenhagen
    2. [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD];
  2. [2] University of St Andrews
    3. [NORA names: United Kingdom; Europe, Non-EU; OECD]

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.

Keywords

SOD1<sup>G93A</sup> mouse model, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis development, amyotrophic lateral sclerosis progression, analysis, attention, circuit, contribution, death, degeneration, detection of transcripts, development, disease, excitatory interneurons, excitatory neurons, image analysis, inhibitory interneurons, inhibitory neurons, interneuron populations, interneurons, intrinsic properties, involvement, lateral sclerosis, machine, machine learning-based image analysis, mice, model, model of amyotrophic lateral sclerosis, motor, motor neuron death, motor neuron degeneration, motor neuron intrinsic properties, motor neurons, mouse model, mouse model of amyotrophic lateral sclerosis, multiplexed detection, multiplexing, neuronal circuits, neuronal death, neuronal degeneration, neuronal intrinsic properties, neurons, observations, population, progression, progressive loss, properties, sclerosis, somatic motor neurons, spinal inhibitory interneurons, spinal inhibitory neurons, spinal interneuron populations, spinal interneurons, spinal neuronal circuits, study, subpopulations, transcription, vulnerability

Funders

  • Lundbeck Foundation
  • Novo Nordisk (Denmark)

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