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Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS

Author

Listed:
  • Santiago Mora

    (University of Copenhagen
    University of St Andrews)

  • Anna Stuckert

    (University of Copenhagen
    University of St Andrews)

  • Rasmus Huth Friis

    (University of Copenhagen)

  • Kimberly Pietersz

    (The Netherlands Institute for Neuroscience)

  • Gith Noes-Holt

    (University of Copenhagen)

  • Roser Montañana-Rosell

    (University of Copenhagen)

  • Haoyu Wang

    (University of St Andrews)

  • Andreas Toft Sørensen

    (University of Copenhagen)

  • Raghavendra Selvan

    (University of Copenhagen)

  • Joost Verhaagen

    (The Netherlands Institute for Neuroscience)

  • Ilary Allodi

    (University of Copenhagen
    University of St Andrews)

Abstract

Loss of connectivity between spinal V1 inhibitory interneurons and motor neurons is found early in disease in the SOD1G93A mice. Such changes in premotor inputs can contribute to homeostatic imbalance of motor neurons. Here, we show that the Extended Synaptotagmin 1 (Esyt1) presynaptic organizer is downregulated in V1 interneurons. V1 restricted overexpression of Esyt1 rescues inhibitory synapses, increases motor neuron survival, and ameliorates motor phenotypes. Two gene therapy approaches overexpressing ESYT1 were investigated; one for local intraspinal delivery, and the other for systemic administration using an AAV-PHP.eB vector delivered intravenously. Improvement of motor functions is observed in both approaches, however systemic administration appears to significantly reduce onset of motor impairment in the SOD1G93A mice in absence of side effects. Altogether, we show that stabilization of V1 synapses by ESYT1 overexpression has the potential to improve motor functions in ALS, demonstrating that interneurons can be a target to attenuate ALS symptoms.

Suggested Citation

  • Santiago Mora & Anna Stuckert & Rasmus Huth Friis & Kimberly Pietersz & Gith Noes-Holt & Roser Montañana-Rosell & Haoyu Wang & Andreas Toft Sørensen & Raghavendra Selvan & Joost Verhaagen & Ilary Allo, 2024. "Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48925-7
    DOI: 10.1038/s41467-024-48925-7
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