
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.30.610545
preprint
1
Article
Synaptic imbalance and increased inhibition impair motor function in SMA
Fletcher Emily V.
Chalif Joshua I.
Rotterman Travis M.
Pagiazitis John G.
Van Alstyne Meaghan
Sivakumar Nandhini
Rabinowitz Joseph E.
Pellizzoni Livio
Alvarez Francisco J.
Mentis George Z. http://orcid.org/0000-0002-4610-2016

01 9 2024
2024.08.30.610545https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.30.610545
nihpp-2024.08.30.610545.pdf
ABSTRACT

Movement is executed through the balanced action of excitatory and inhibitory neurotransmission in motor circuits of the spinal cord. Short-term perturbations in one of the two types of transmission are counteracted by homeostatic changes of the opposing type. Prolonged failure to balance excitatory and inhibitory drive results in dysfunction at the single neuron, as well as neuronal network levels. However, whether dysfunction in one or both types of neurotransmission leads to pathogenicity in neurodegenerative diseases characterized by select synaptic deficits is not known. Here, we used mouse genetics, functional assays, morphological methods, and viral-mediated approaches to uncover the pathogenic contribution of unbalanced excitation-inhibition neurotransmission in a mouse model of spinal muscular atrophy (SMA). We show that vulnerable motor circuits in the SMA spinal cord fail to respond homeostatically to the reduction of excitatory drive and instead increase inhibition. This imposes an excessive burden on motor neurons and further restricts their recruitment to activate muscle contraction. Importantly, genetic or pharmacological reduction of inhibitory synaptic drive improves neuronal function and provides behavioural benefit in SMA mice. Our findings identify the lack of excitation-inhibition homeostasis as a major maladaptive mechanism in SMA, by which the combined effects of reduced excitation and increased inhibition diminish the capacity of premotor commands to recruit motor neurons and elicit muscle contractions.
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pmc
