Trpm5 channels encode bistability of spinal motoneurons and ensure motor control of hindlimbs in mice

Abstract

Bistable motoneurons of the spinal cord exhibit warmth-activated plateau potential driven by Na+ and triggered by a brief excitation. The thermoregulating molecular mechanisms of bistability and their role in motor functions remain unknown. Here, we identify thermosensitive Na+-permeable Trpm5 channels as the main molecular players for bistability in mouse motoneurons. Pharmacological, genetic or computational inhibition of Trpm5 occlude bistable-related properties (slow afterdepolarization, windup, plateau potentials) and reduce spinal locomotor outputs while central pattern generators for locomotion operate normally. At cellular level, Trpm5 is activated by a ryanodine-mediated Ca2+ release and turned off by Ca2+ reuptake through the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump. Mice in which Trpm5 is genetically silenced in most lumbar motoneurons develop hindlimb paresis and show difficulties in executing high-demanding locomotor tasks. Overall, by encoding bistability in motoneurons, Trpm5 appears indispensable for producing a postural tone in hindlimbs and amplifying the locomotor output.

Astrocytes regulate locomotion by orchestrating neuronal rhythmicity in the spinal network via potassium clearance

“…We did not observe any Kir4.1-ShRNA expression in brain or brainstem structures involved in the locomotor control. This result is in line with the restricted diffusion to the thoraco-lumbar segments of the AAV9-ShRNA injected intrathecally at birth in the lumbar segments (Bos et al, 2021). Thus we assume that the behavioural consequence of Kir4.1 knockdown on locomotor performances is due to Kir4.1 decrease in the spinal locomotor networks.…”

Persistent Nav1.6 current drives spinal locomotor functions through nonlinear dynamics

“…From a dose-response curve the optimal concentration was established at 350 nM for ICA and 200nM for 4,9-ahTTX (Figure S2). As we previously reported 16,19 , most of the large motoneurons (~90 %) displayed a self-sustained spiking activity dependent on I NaP and triggered by a brief excitation (Figure 2A). This bistability was insensitive to ICA but abolished by 4,9-ahTTX (Figure 2B-D).…”

“…Beyond its rhythmogenic role, I NaP also amplifies synaptic transmission by enabling self-sustained spiking activity triggered in spinal motoneurons by a brief excitation [16][17][18] . This bistable behavior has recently been shown to be a cellular correlate of the postural tone in hindlimbs 19 . In sum, in agreement with motor dysfunctions often associated with its alteration [20][21][22][23][24][25][26] , I NaP appears to be critical for the operation of the spinal locomotor network in vertebrates.…”

“…Therefore, the substantial drop in I NaP following the deletion of Nav1.6 offers a biophysical basis for the lower capacity of motoneurons to spike tonically. Collectively, a scenario arises where the persistent Nav1.6 current leads to a mechanism of self-maintaining motoneuronal output as follow: secondary to the recruitment of Ca 2+ channels during repetitive spikes, Nav1.6-mediated I NaP indirectly fuel motoneurons in Ca 2+ to activate Trpm5 channels governing a plateau potential responsible for the self-sustained spiking 16,19 . By virtue of this recruitment cascade, Nav1.6 channels serve as the gateway to self-sustained spiking allowing efficient postural tone in muscles.…”

Voluntary activation of muscle in humans: does serotonergic neuromodulation matter?

“…In mammals, there are believed to be equal contributions from slow activating L‐type Ca 2+ current and a fast activating persistent Na + current to the PIC (Heckman, Hyngstrom et al., 2008). However, recent evidence shows that non‐linearities in motoneurone discharge may have more complex mechanisms including activation of TRPm5 and inactivation of Kv1.2 channels (Bos et al., 2018; Bos et al., 2021). Nonetheless, PICs are strongly influenced by monoamines.…”