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bioRxiv · 10.1101/2025.06.06.658369

Ionic Mechanisms Underlying Bistability in Spinal Motoneurons: Insights from a Computational Model

Molkov, Y.·Krust, F.·Jeter, R.·Stell, T.·Mohammed, M. A. Y.·Brocard, F.·Rybak, I.
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Abstract

Spinal motoneurons are the final output of spinal circuits that engage skeletal muscles to generate motor behaviors. Many motoneurons exhibit bistable behavior, alternating between a quiescent resting state and a self-sustained firing mode, classically attributed to plateau potentials driven by persistent inward currents. This intrinsic property is important for normal movement control, but can become dysregulated, causing motor function deficits, like spasticity. Here we use a conductance-based single-compartment model, together with mouse spinal slice recordings,to investigate the ionic interactions underlying motoneuron bistability. We show that synergistic interactions among high-voltage-activated L-type Ca2+ current (ICaL), calcium-induced calcium release (CICR) and the Ca2+-activated non-specific cation current (ICAN) constitute a minimal mechanistic core that produces plateau potentials and bistable firing. Within this framework, the persistent sodium current (INaP) promotes plateau generation, in contrast to the Ca2+-dependent K+ current (IKCa) which opposes it. These results delineate ionic dependencies at the level of interactions rather than spatial localisation and provide a tractable basis for interpreting altered motoneuron excitability in disease. Key PointsO_LIWe investigated how spinal motoneurons, critical for skeletal muscle control, exhibit bistability, switching between quiet and self-sustained firing. This property stabilizes motor functions like postural control, and its dysregulation contributes to disorders such as spasticity. Using a single-compartment computational model and mouse spinal slice recordings, we explored the ionic interactions driving bistability. C_LIO_LIOur findings reveal that a calcium-activated cation non-specific current and calcium-induced calcium release form a core mechanism supporting the plateau depolarization essential for bistable firing. Within this framework, the persistent sodium current facilitates plateau generation, while the calcium-dependent potassium current counteracts it. Pharmacological manipulations in slices yielded results consistent with these current roles. C_LIO_LIOur study delineates the ionic dependencies of motoneuron bistability based on interactions, not spatial location. This offers a concise framework for interpreting excitability changes observed in normal conditions and following spinal cord injury, providing valuable insights into motor function and neurological disorders. C_LI

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Molkov, Y., Krust, F., Jeter, R., Stell, T., Mohammed, M. A. Y., Brocard, F., Rybak, I.. 2025-06-10. Ionic Mechanisms Underlying Bistability in Spinal Motoneurons: Insights from a Computational Model. https://doi.org/10.1101/2025.06.06.658369

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