Journal Article

DZNE-2026-00414

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Motoneurons Inhibitory Synapses Homeostatically Respond to Neuronal Activity and Modulate Amyotrophic Lateral Sclerosis Pathogenesis.

Halablab, K. (First author)DZNE* ; Yartas, G.DZNE* ; Dikwella, N. ; Aousji, O. ; Ozkan, B. ; Jan, C. ; Wiesner, D.DZNE* ; Danner, S. M. ; Caron, G. ; Zytnicki, D. ; Roselli, F. (Last author)DZNE*

2026
Soc. Washington, DC

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Please use a persistent id in citations: doi:10.1523/JNEUROSCI.0011-25.2026

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 versus 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.

Keyword(s): Animals (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Amyotrophic Lateral Sclerosis: physiopathology (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Motor Neurons: physiology (MeSH) ; Motor Neurons: pathology (MeSH) ; Synapses: physiology (MeSH) ; Mice (MeSH) ; Male (MeSH) ; Mice, Transgenic (MeSH) ; Neural Inhibition: physiology (MeSH) ; Homeostasis: physiology (MeSH) ; Humans (MeSH) ; Superoxide Dismutase: genetics (MeSH) ; amyotrophic lateral sclerosis ; chemogenetics ; excitation ; inhibitory synapses ; intrabodies ; motoneurons ; Superoxide Dismutase

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Contributing Institute(s):

1. Metabolic Changes in Neurodegeneration (AG Roselli)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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