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Synaptic imbalance and increased inhibition impair motor function in SMA
Emily V Fletcher1,2, Joshua I Chalif1,2, Travis M Rotterman3
1Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
Science Advances
|September 5, 2025
Summary
In spinal muscular atrophy (SMA), motor circuits fail to balance excitation and inhibition, leading to motor neuron dysfunction. Reducing inhibition improves motor function in SMA mice.
Area of Science:
- Neuroscience
- Motor Control
- Neurodegenerative Diseases
Background:
- Balanced excitation-inhibition is crucial for spinal motor circuit function.
- Prolonged imbalance leads to neuronal and circuit dysfunction.
- The role of excitation-inhibition imbalance in neurodegenerative diseases with synaptic deficits is unclear.
Purpose of the Study:
- To investigate the pathogenic contribution of unbalanced excitation-inhibition in a mouse model of spinal muscular atrophy (SMA).
- To understand how excitation-inhibition homeostasis is disrupted in SMA motor circuits.
Main Methods:
- Functional, morphological, and viral-mediated approaches were used.
- A mouse model of spinal muscular atrophy (SMA) was employed.
- Genetic and pharmacological interventions were utilized to reduce inhibition.
Main Results:
- SMA motor circuits exhibit impaired homeostatic response to reduced excitation, increasing inhibition instead.
- This increased inhibition burdens motor neurons and restricts their recruitment.
- Reducing inhibition ameliorated neuronal function and improved motor behavior in SMA mice.
Conclusions:
- Disrupted excitation-inhibition homeostasis is a key maladaptive mechanism in SMA.
- This imbalance limits the recruitment of motor neurons and muscle contraction.
- Targeting inhibition offers a therapeutic strategy for SMA.
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