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Spinal circuit mechanisms constrain therapeutic windows for ALS intervention: A computational modeling study
Beck Strohmer1, Kaitlyn Grosh2, Roser Montañana-Rosell3
1Department of Neuroscience, University of Copenhagen, Blegdamsvej 3B Copenhagen 2200, Denmark.
Neurobiology of Disease
|January 1, 2026
Summary
Stabilizing inhibitory V1 interneuron connections in Amyotrophic Lateral Sclerosis (ALS) can preserve motor function and rescue excitatory V2a interneurons. Optimal timing is crucial, as late interventions may become ineffective due to network changes.
Area of Science:
- Neuroscience
- Computational Biology
- Systems Biology
Background:
- Amyotrophic Lateral Sclerosis (ALS) involves motoneuron death and neurodegeneration.
- Dysregulation of inhibitory V1 interneurons precedes V2a interneuron and motoneuron loss in ALS.
- Previous studies showed V1-motoneuron connection stabilization improved motor function in an ALS mouse model.
Purpose of the Study:
- To determine the optimal timing for V1 interneuron-based interventions in ALS.
- To model spinal locomotor circuits to understand ALS progression and therapeutic intervention effects.
- To investigate the impact of V1 dysregulation on motoneuron output and flexor-extensor coordination.
Main Methods:
- Development of a spiking neural network model of spinal locomotor circuits.
- Simulation of healthy and ALS-like conditions, including network connectivity and synaptic dynamics changes.
- Experimental validation in the SOD1G93A ALS mouse model.
Main Results:
- V1 dysregulation leads to flexor-biased motoneuron activity and disrupted coordination.
- V1 synapse stabilization preserved motor output even with motoneuron loss, suggesting therapeutic potential in symptomatic stages.
- Late-stage intervention with V1 stabilization may lead to maladaptive activity due to synaptic changes.
- V1 stabilization rescued V2a excitatory interneurons, confirmed experimentally.
Conclusions:
- Spinal circuit modeling provides a framework for identifying therapeutic time windows for ALS interventions.
- Excitatory/inhibitory balance is critical for the effectiveness of V1 stabilization therapies.
- Intervention timing is a key factor for successful therapeutic outcomes in ALS preclinical studies.
