Activity-Dependent Changes in Extracellular Ca2+ and K+ Reveal Pacemakers in the Spinal Locomotor-Related Network

SummaryChanges in the extracellular ionic concentrations occur as a natural consequence of firing activity in large populations of neurons. The extent to which these changes alter the properties of individual neurons and the operation of neuronal networks remains unknown. Here, we show that the locomotor-like activity in the isolated neonatal rodent spinal cord reduces the extracellular calcium ([Ca2+]o) to 0.9 mM and increases the extracellular potassium ([K+]o) to 6 mM. Such changes in [Ca2+]o and [K+]o trigger pacemaker activities in interneurons considered to be part of the locomotor network. Experimental data and a modeling study show that the emergence of pacemaker properties critically involves a [Ca2+]o-dependent activation of the persistent sodium current (INaP). These results support a concept for locomotor rhythm generation in which INaP-dependent pacemaker properties in spinal interneurons are switched on and tuned by activity-dependent changes in [Ca2+]o and [K+]o

Histamine modulates spinal motoneurons and locomotor circuits

Spinal motoneurons and locomotor networks are regulated by monoamines, among which, the contribution of histamine has yet to be fully addressed. The present study investigates histaminergic regulation of spinal activity, combining intra- and extracellular electrophysiological recordings from neonatal rat spinal cord in vitro preparations. Histamine dose-dependently and reversibly generated motoneuron depolarization and action potential firing. Histamine (20μM) halved the area of dorsal root reflexes and always depolarized motoneurons. The majority of cells showed a transitory repolarization, while 37% showed a sustained depolarization maintained with intense firing. Extracellularly, histamine depolarized ventral roots (VRs), regardless of blockage of ionotropic glutamate receptors. Initial, transient glutamate-mediated bursting was synchronous among VRs, with some bouts of locomotor activity in a subgroup of preparations. After washout, the amplitude of spontaneous tonic discharges increased. No desensitization or tachyphylaxis appeared after long perfusion or serial applications of histamine. On the other hand, histamine induced single motoneuron and VR depolarization, even in the presence of tetrodotoxin (TTX). During chemically induced fictive locomotion (FL), histamine depolarized VRs. Histamine dose-dependently increased rhythm periodicity and reduced cycle amplitude until near suppression. This study demonstrates that histamine induces direct motoneuron membrane depolarization and modulation of locomotor output, indicating new potential targets for locomotor neurorehabilitation

Sensitization and Interoception as Key Neurological Concepts in Osteopathy and Other Manual Medicines

Historically, approaches used in manual medicine to explain patient reported symptoms have been focused on the so-called exteroceptive paradigm. Arguably, this mindset lacks an appropriate "reading system" able to interpret musculoskeletal disorders from a different perspective, where the properties of the nervous system are embraced into a more holistic and functional-related context. Interestingly, if the underpinning mechanisms of a given treatment scenario/effect are taking into account, the majority of research outcomes focuses on a proprioceptive/exteroceptive explanation, leaving ting aside the additional or even central role of interoception. Currently, to date, the application of theoretical knowledge acquired on the relatively recent neuroscientific concepts and evidence concerning of interoception, sensitization, touch, autonomic functions, inflammation, and pain into a clinical/research manual medicine scenario is lacking, even if theoretically, the impact on the possible etiological mechanisms and treatment effects seems to be important. Here, we propose the conceptual foundations for a new way of interpreting and reading patients' clinical reported outcomes scenario based on interoception and sensitization. We argue that this will provide a foundation to create the ground for future research focusing on the hypotheses that manual therapies, specifically osteopathy, can intercede with sensitization states, at all levels, using interoceptive pathways

Bistable properties of spinal motoneurons : Identification of underlying mechanism

La posture, composante statique du contrôle moteur permettant une position érigée du corps, repose sur une décharge tonique des motoneurones innervant nos muscles antigravitaires. La décharge prend la forme de « potentiel de plateau » au niveau de motoneurones matures chez de nombreux vertébrés. Pour déterminer une éventuelle concordance entre l'émergence des propriétés de plateau et le développement postural, notre travail a eu pour but d'étudier la maturation et la nature ionique des potentiels de plateau des motoneurones innervant le muscle triceps surae (extenseur de la cheville) chez le rat nouveau-né.La réalisation de ces travaux de thèse nous a permis de dégager un mécanisme fondamental dans la genèse des propriétés de plateau des motoneurones lombaires. Ce mécanisme dont le fondement repose sur l'activation d'un « ménage à trois » jouerait un rôle majeur dans le développement moteur chez le rat. Dans la mesure où les potentiels de plateau des motoneurones sont fortement perturbés à la suite d'une lésion médullaire, cette avancée scientifique permettra éventuellement de mieux comprendre l'origine de certains déficits sensori-moteurs (spasticité, hyperalgésie...) et le développement de nouvelles stratégies thérapeutiques.Posture allowing an erect posture of the body relies on spiking activity of motoneurons innervating antigravitary muscle. Discharge could take the form of plateau potential on mature motoneurons of numerous vertebrates. To determine a possible concordance between the emergence of plateau potential and postural control development, we studied the maturation and ionic nature of plateau potential of motoneurons innervating triceps surae muscle of neonatal rat.The conclusion of our work allows us to propose a fundamental mechanism in the genesis of plateau potential on lumbar motoneurons. This mechanism based on a "ménage a trois" seems to play an important role in the neonatal motor development. This scientific advance could eventually lead to a better understanding of the origin of some sensori-motor impairments (spasticity, hyperalgesia...) and development of therapeutic strategies

Sensitization of neonatal rat lumbar motoneuron by the inflammatory pain mediator bradykinin

International audienceBradykinin (Bk) is a potent inflammatory mediator that causes hyperalgesia. The action of Bk on the sensory system is well documented but its effects on motoneurons, the final pathway of the motor system, are unknown. By a combination of patch-clamp recordings and two-photon calcium imaging, we found that Bk strongly sensitizes spinal motoneurons. Sensitization was characterized by an increased ability to generate self-sustained spiking in response to excitatory inputs. Our pharmacological study described a dual ionic mechanism to sensitize motoneurons, including inhibition of a barium-sensitive resting K + conductance and activation of a nonselective cationic conductance primarily mediated by Na +. Examination of the upstream signaling pathways provided evidence for postsynaptic activation of B 2 receptors, G protein activation of phospholipase C, InsP3 synthesis, and calmodulin activation. This study questions the influence of motoneurons in the assessment of hyperalgesia since the withdrawal motor reflex is commonly used as a surrogate pain model

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

International audienceAbstract 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 Ca 2+ release and turned off by Ca 2+ reuptake through the sarco/endoplasmic reticulum Ca 2+ -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

Cleavage of Na+ channels by calpain increases persistent Na+ current and promotes spasticity after spinal cord injury

International audienceUpregulation of the persistent sodium current (INaP) in motoneurons contributes to spasticity following spinal cord injury (SCI). We investigated the mechanisms that regulate INaP and observed elevated expression of Nav1.6 channels in spinal lumbar motoneurons of adult rats with SCI. Furthermore, immunoblot revealed a proteolysis of Nav channels and biochemical assays identified calpain as the main proteolytic factor. Calpain-dependent cleavage of Nav channels following neonatal SCI was associated with an upregulation of INaP in motoneurons. Likewise, calpain-dependent cleavage of Nav1.6 channels expressed in HEK-293 cells caused elevation of INaP. Pharmacological inhibition of calpain by MDL28170 reduced the cleavage of Nav channels, INaP in motoneurons and spasticity in rats with SCI. Similarly, blockade of INaP by riluzole alleviated spasticity. This study demonstrates that Nav channel expression in lumbar motoneurons is altered after SCI and shows a tight relationship between the calpain-dependent proteolysis of Nav1.6 channels, the upregulation of INaP and spasticity