Krust, F. | bioRxiv Science

bioRxiv2026

SK2/3 CHANNELS COUPLE WITH T-TYPE CA2+ CHANNELS TO GATE SPINAL LOCOMOTOR RHYTHM GENERATION

Initiating locomotion requires central pattern generator (CPG) interneurons to transition from tonic firing to persistent sodium current (INaP)-dependent bursting. While INaP provides the rhythmogenic drive, the conductances gating this transition remain unclear. Here, we show that functional coupling between small-conductance calcium-activated potassium (SK2/3) channels and low-threshold T-type Ca2+ channels, notably Cav3.2, gates locomotor rhythm generation. Pharmacological or genetic disruption of this SK-T-type axis triggers intrinsic bursting in Hb9 interneurons, a genetically identified rhythmogenic population of the locomotor CPG, and initiates fictive locomotion, whereas SK activation silences ongoing rhythmic output. Immunohistochemical co-expression of SK2, SK3 and Cav3.2 in Hb9 interneurons provides an anatomical basis for this functional coupling. Simulation-based inference further shows that, beyond this gating mechanism, burst diversity is primarily determined by the balance between INaP and M-type potassium conductances. Together, these findings identify SK-T-type coupling as a tunable brake on CPG activation, defining a biophysical module that controls the initiation and termination of locomotor rhythmic activity, with potential relevance for rhythmogenic circuits beyond locomotion.

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bioRxiv2025

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

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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