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Motoneurons inhibitory synapses homeostatically respond to neuronal activity and modulate Amyotrophic Lateral Sclerosis pathogenesis
Journal article   Peer reviewed

Motoneurons inhibitory synapses homeostatically respond to neuronal activity and modulate Amyotrophic Lateral Sclerosis pathogenesis

Kareen Halablab, Gizem Yartas, Natalie Dikwella, Oumayma Aousji, B Ozkan, Cedric Jan, Diana Wiesner, Simon M Danner, Guillaume Caron, Daniel Zytnicki, …
The journal of neuroscience : the official journal of the Society for Neuroscience, e0011252026
12 Mar 2026
DOI: https://doi.org/10.1523/JNEUROSCI.0011-25.2026
PMID: 41819843
Featured in Collection :   Drexel's Newest Publications

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.

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