Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS
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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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 4867 |
| Tidsskrift | Nature Communications |
| Vol/bind | 15 |
| Udgave nummer | 1 |
| Sider (fra-til) | 1-16 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
We thank Prof. Ole Kiehn, Department of Neuroscience \u2013 University of Copenhagen, for the access to the surgery room and the use of the DigiGait treadmill. We acknowledge the Core Facility for Integrated Microscopy (CFIM), at the Faculty of Health and Medical Science of University of Copenhagen and the Department of Experimental Medicine (AEM), especially Dr. Pablo Hernandez-Varas (CFIM) and Alex Soelberg Laugesen (AEM). This work was supported by the Lundbeck Foundation (R346-2020-2025, I.A.), the Louis-Hansen Foundation (21-2B-9477/L102, I.A. and 18-2B-3570, R.M.R.), the Danish Society for ALS (1214371001, I.A.), the Laege Sofus Carl Emil Friis og hustru Olga Doris Friis\u2019 foundation (1218471001, I.A.), the Danish Society for Neuroscience (DSFN2020-5, R.F. and DSFN2022-3, A.S.), a grant from the research fund of the Royal Netherlands Academy for Arts and Sciences (KNAW - koninklijke academie van Wetenschappen, BDO1095, J.V.), the Department of Neuroscience at University of Copenhagen (I.A.), the School of Psychology and Neuroscience at University of St Andrews (I.A.) and the St Leonard\u2019s college PhD Scholarships (W7, I.A.).
Publisher Copyright:
© The Author(s) 2024.
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