Journal article
Motoneurons inhibitory synapses homeostatically respond to neuronal activity and modulate Amyotrophic Lateral Sclerosis pathogenesis
The journal of neuroscience : the official journal of the Society for Neuroscience, v 46(15), e0011252026
12 Mar 2026
PMID: 41819843
Abstract
Alterations in Excitation/inhibition (E/I) balance and changes in motor neurons (MN) activity may contribute to MN vulnerability in ALS. The balance of pathogenic vs adaptive changes occurring in inhibitory synapses and affecting E/I balance remain unclear. Confocal microscopy of MN from P45 male SOD1G93A mice reveal downregulated GlyR but upregulated GABAR clusters at inhibitory synapses. GlyR and GABAR respond to PSAM and DREADD chemogenetic alterations of MN excitability, with increased activity driving increase in inhibitory clusters. An E3 ligase-conjugated intrabody (GFE3) degrades Gephyrin, decreases GABAR and GlyR clusters, increases net activity and downregulates disease markers. However, simultaneous decrease of inhibition and increased activity by actPSAM and GFE3 shows no net beneficial effects on disease markers. Thus inhibitory synapses are involved in the early phases of ALS pathogenesis and respond to persistent homeostatic loops and their suppression delivers a net activity increase, offering potential benefits on disease pathways.
Metrics
6 Record Views
Details
- Title
- Motoneurons inhibitory synapses homeostatically respond to neuronal activity and modulate Amyotrophic Lateral Sclerosis pathogenesis
- Creators
- Kareen Halablab - Universität UlmGizem Yartas - German Center for Neurodegenerative DiseasesNatalie Dikwella - Universität UlmOumayma Aousji - Universität UlmB OzkanCedric Jan - Universität UlmDiana Wiesner - German Center for Neurodegenerative DiseasesSimon M Danner - Drexel University, Neurobiology and AnatomyGuillaume Caron - Université Paris CitéDaniel Zytnicki - Université Paris CitéFrancesco Roselli - German Center for Neurodegenerative Diseases
- Publication Details
- The journal of neuroscience : the official journal of the Society for Neuroscience, v 46(15), e0011252026
- Publisher
- SOC NEUROSCIENCE
- Number of pages
- 14
- Grant note
- ANR/Deutsche ForschungsGemeinschaft grant "SynaptALS": DFG NR. 446067541, ANR-20-CE92-0029-01 DFG: 443642953, 431995586 German Center for Neurodegenerative Diseases (DZNE)-Ulm core funding Thierry-Latran Foundation (TRiALS grant) Radala Foundation
This work was supported by the ANR/Deutsche ForschungsGemeinschaft grant "SynaptALS" to F.R. (DFG NR. 446067541) and to D.Z. (ANR-20-CE92-0029-01) ; F.R. was also supported by the DFG with the grant nos. 443642953 and 431995586. K.H. is also supported by the German Center for Neurodegenerative Diseases (DZNE)-Ulm core funding. D.Z. and F.R. were also supported by the Thierry-Latran Foundation (TRiALS grant) and by the Radala Foundation. F.R. and K.H. thank the colleagues of the DZNE, in particular Dr. Jelena Scekic-Zahirovic, for helpful discussion and contributions. We thank the staff scientists Thomas Lenk, Florian olde Heuvel, and the assistant students Sarah Higgins and Rebecca Asbahr for their technical support. We also thank Prof. Tobias Boeckers for providing the anti-Shank antibodies.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:001750319900001
- Scopus ID
- 2-s2.0-105035860886
- Other Identifier
- 991022165638104721