Spatiotemporal correlation of spinal network dynamics underlying spasms in chronic spinalized mice

Abstract

Spasms after spinal cord injury (SCI) are debilitating involuntary muscle contractions that have been associated with increased motor neuron excitability and decreased inhibition. However, whether spasms involve activation of premotor spinal excitatory neuronal circuits is unknown. Here we use mouse genetics, electrophysiology, imaging and optogenetics to directly target major classes of spinal interneurons as well as motor neurons during spasms in a mouse model of chronic SCI. We find that assemblies of excitatory spinal interneurons are recruited by sensory input into functional circuits to generate persistent neural activity, which interacts with both the graded expression of plateau potentials in motor neurons to generate spasms, and inhibitory interneurons to curtail them. Our study reveals hitherto unrecognized neuronal mechanisms for the generation of persistent neural activity under pathophysiological conditions, opening up new targets for treatment of muscle spasms after SCI.DOI: http://dx.doi.org/10.7554/eLife.23011.001

A Latent Propriospinal Network Can Restore Diaphragm Function after High Cervical Spinal Cord Injury

“…Two well-described cases of increased network excitability exist physiologically: First, during embryogenesis, spinal circuits are highly excitable due to depolarizing action of GABA/glycine (Jean-Xavier et al, 2007). Second, spinal cord injury results in a variety of membrane and/or synaptic changes as well as anatomical remodeling that causes increased network excitability (Bellardita et al, 2017; Buttry and Goshgarian, 2014). …”

“…Increased excitation after spinal cord injury can lead to adverse outcomes, including muscle spasticity and/or autonomic dysreflexia (Bellardita et al, 2017; Ueno et al, 2016). An emergent view is that spasticity is caused by recruitment of disparate populations of excitatory neurons into functional circuits—leading to enhanced excitation independent of motor neuron excitability or inhibition (Bellardita et al, 2017).…”

“…An emergent view is that spasticity is caused by recruitment of disparate populations of excitatory neurons into functional circuits—leading to enhanced excitation independent of motor neuron excitability or inhibition (Bellardita et al, 2017). Interestingly, cervical spinal cord injury in human C4 tetraplegic patients is sometimes accompanied by diaphragm spasticity (Silver and Lehr, 1981).…”

Une nouvelle cible thérapeutique dans le traitement de la spasticité après une lésion de la moelle épinière : la calpaïne

“…Les spasmes se manifestent par des co-contractions de muscles fonctionnellement opposées (Figure 1b), rendant tout mouvement volontaire difficile. De tels spasmes musculaires peuvent égale-ment être évoqués dans des modèles expérimentaux de rats [6] ou de souris [7] médullo-lésés. La spasticité a donc des conséquences importantes sur la qualité de vie, puisqu'elle réduit significativement la mobilité, les soins corporels, le sommeil, la fonction sexuelle, et l'estime de soi [8].…”

Nimodipine prevents the development of spasticity after spinal cord injury

“…L-type calcium currents represent a major component of the persistent inward currents (PICs) underlying plateau potentials, a membrane property that allows neurons to sustain firing with little or no synaptic inputs (11)(12)(13). The expression of plateau potentials is enhanced in spinal neurons during the chronic phase of SCI with a direct correlation between expression of plateau potentials and appearance of spasticity (12,(14)(15)(16). In addition to a role in membrane excitability, L-type voltage-gated calcium channels are involved in calcium signaling and calcium-induced gene expression in neurons (17).…”