Spinal circuit mechanisms constrain therapeutic windows for ALS intervention: A computational modeling study

TL;DR

This study uses a computational model to explore how spinal circuit imbalances affect ALS progression and identifies optimal timing for interventions.

Contribution

A computational model reveals how V1 interneuron dysregulation affects motor output and defines a therapeutic window for synaptic stabilization in ALS.

Findings

Flexor-biased activity arises from imbalances in spinal circuits due to V1 interneuron dysregulation.

Synaptic stabilization can rescue V2a interneurons and preserve motor function in early symptomatic stages.

There is a limited temporal window for effective synaptic intervention before maladaptive activity emerges.

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive breakdown of neural circuits which leads to motoneuron death. Earlier work from our lab showed that dysregulation of inhibitory V1 interneurons precedes the degeneration of excitatory V2a interneurons and motoneurons and that stabilizing V1–motoneuron connections improved motor function and saved motoneurons in the SOD1G93A ALS mouse model. However, the optimal timing for this intervention remains unclear. To address this, we developed a spiking neural network model of spinal locomotor circuits to simulate healthy and ALS-like conditions. By modeling changes in network connectivity and synaptic dynamics, we predict that V1 dysregulation induces an imbalance in motoneuron output which results in flexor-biased activity, leading to the disruption of flexor–extensor coordination, and potentially contributing to selective vulnerability of flexor motoneurons. Stabilizing V1 synapses preserved motor output even after motoneuron loss, suggesting that therapeutic benefit is possible into symptomatic stages. However, model predictions also highlighted that after sustained synaptic loss and the development of slower synaptic dynamics within the network, synaptic stabilization leads to maladaptive extensor-biased activity, suggesting that excitatory/inhibitory balance impacts treatment effectiveness. Finally, the model indicated that V1 stabilization could lead to rescue of the V2a excitatory interneurons, a finding that we were able to confirm experimentally in the SOD1G93A ALS mouse model. By exploring different scenarios of synaptic loss and cell dysregulation during synaptic stabilization, our models provide a framework for predicting candidate time windows for spinal circuit interventions, which may guide future preclinical investigations.

•Flexor-biased output may be a consequence of network asymmetries.•ALS may differentially affect flexor and extensor motoneurons.•V2a interneurons are rescued after synaptic stabilization.•There exists a temporal window for maximally effective synaptic intervention.

Flexor-biased output may be a consequence of network asymmetries.

ALS may differentially affect flexor and extensor motoneurons.

V2a interneurons are rescued after synaptic stabilization.

There exists a temporal window for maximally effective synaptic intervention.

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