Biology subjects

Cote, M.-P.

Publications and source records attributed to Cote, M.-P..

5 recordsLinked to original sources

bioRxiv2023

Multi-session transcutaneous spinal cord stimulation prevents chloride homeostasis imbalance and the development of spasticity after spinal cord injury in rat

Spasticity is a complex and multidimensional disorder that impacts nearly 75% of individuals with spinal cord injury (SCI) and currently lacks adequate treatment options. This sensorimotor condition is burdensome as hyperexcitability of reflex pathways result in exacerbated reflex responses, co-contractions of antagonistic muscles, and involuntary movements. Transcutaneous spinal cord stimulation (tSCS) has become a popular tool in the human SCI research field. The likeliness for this intervention to be successful as a noninvasive anti-spastic therapy after SCI is suggested by a mild and transitory improvement in spastic symptoms following a single stimulation session, but it remains to be determined if repeated tSCS over the course of weeks can produce more profound effects. Despite its popularity, the neuroplasticity induced by tSCS also remains widely unexplored, particularly due to the lack of suitable animal models to investigate this intervention. Thus, the basis of this work was to use tSCS over multiple sessions (multi-session tSCS) in a rat model to target spasticity after SCI and identify the long-term physiological improvements and anatomical neuroplasticity occurring in the spinal cord. Here, we show that multi-session tSCS in rats with an incomplete (severe T9 contusion) SCI (1) decreases hyperreflexia, (2) increases the low frequency-dependent modulation of the H-reflex, (3) prevents potassium-chloride cotransporter isoform 2 (KCC2) membrane downregulation in lumbar motoneurons, and (4) generally augments motor output, i.e., EMG amplitude in response to single pulses of tSCS, particularly in extensor muscles. Together, this work displays that multi-session tSCS can target and diminish spasticity after SCI as an alternative to pharmacological interventions and begins to highlight the underlying neuroplasticity contributing to its success in improving functional recovery.

neuroscience↗

bioRxiv2023

KCC2 Enhancers Normalize Reflex Responses and Improve Locomotor Function after Chronic Spinal Cord Injury

Within a year after a spinal cord injury (SCI), 75% of individuals develop spasticity. While normal movement relies on the ability to adjust reflexes appropriately, and on reciprocal inhibition of antagonistic muscles, spastic individuals display hyperactive spinal reflexes and involuntary muscle co-contractions. Current anti-spastic medications can suppress uncontrolled movements, but by acting on GABAergic signalling, these medications lead to severe side-effects and weakened muscle force, making them incompatible with activity-based therapies. We have previously shown that pharmacologically enhancing activity of KCC2, a chloride cotransporter, reduces signs of spasticity in anesthetized chronic SCI rats. Here, we examine the effect of enhancing KCC2 in awake animals, using a battery of tests to assess multiple reflex pathways required for normal movement as well as locomotor function. Sprague-Dawley rats were implanted with chronic EMG electrodes bilaterally in ankle flexor and ankle extensor muscles and received a complete spinal transection at T12. Four weeks following SCI, the stretch reflex, the non-nociceptive cutaneous reflex pathway, the flexor withdrawal reflex, and the crossed-extensor reflex pathway as well as locomotor function were evaluated before and after receiving the KCC2 enhancer, CLP290. Our results show that enhancing KCC2 activity normalizes reflex responses in multiple pathways and reduces muscle co-contraction without weakening motor output, thereby improving stepping ability. This work reveals the substantial potential for KCC2 enhancers as a novel antispastic treatment.

neuroscience↗

bioRxiv2020

Direct evidence for decreased presynaptic inhibition evoked by PBSt group I muscle afferents after chronic SCI and recovery with step-training in the decerebrated rat

Spinal cord injury (SCI) results in the disruption of supraspinal control of spinal networks and an increase in the relative influence of afferent feedback to sublesional neural networks, both of which contribute to enhancing spinal reflex excitability. Hyperreflexia occurs in ~75% of individuals with chronic SCI and critically hinders functional recovery and quality of life. It is suggested to result from an increase in motoneuronal excitability and a decrease in presynaptic and postsynaptic inhibitory mechanisms. In contrast, locomotor training decreases hyperreflexia by restoring presynaptic inhibition. Primary afferent depolarization (PAD) is a powerful presynaptic inhibitory mechanism that selectively gates primary afferent transmission to spinal neurons to adjust reflex excitability and ensure smooth movement. However, the effect of chronic SCI and step-training on the reorganization of presynaptic inhibition evoked by hindlimb afferents, and the contribution of PAD has never been demonstrated. The objective of this study is to directly measure changes in presynaptic inhibition through dorsal root potentials (DRPs) and its association to plantar H-reflex inhibition. We provide direct evidence that H-reflex hyperexcitability is associated with a decrease in transmission of PAD pathways activated by PBSt afferents after chronic SCI. More precisely, we illustrate that PBSt group I muscle afferents evoke a similar pattern of inhibition onto both L4-DRPs and plantar H-reflexes evoked by the tibial nerve in Control and step-trained animals, but not in chronic SCI rats. These changes are not observed after step-training, suggesting a role for activity-dependent plasticity to regulate PAD pathways activated by flexor muscle group I afferents. Key point summaryO_LIPresynaptic inhibition is modulated by supraspinal centers and primary afferents in order to filter sensory information, adjust spinal reflex excitability, and ensure smooth movements. C_LIO_LIAfter SCI, the supraspinal control of primary afferent depolarization (PAD) interneurons is disengaged, suggesting an increased role for sensory afferents. While increased H-reflex excitability in spastic individuals indicates a possible decrease in presynaptic inhibition, it remains unclear whether a decrease in sensory-evoked PAD contributes to this effect. C_LIO_LIWe investigated whether the PAD evoked by hindlimb afferents contributes to the change in presynaptic inhibition of the H-reflex in a decerebrated rat preparation. We found that chronic SCI decreases presynaptic inhibition of the plantar H-reflex through a reduction in PAD evoked by PBSt muscle group I afferents. C_LIO_LIWe further found that step-training restored presynaptic inhibition of the plantar H-reflex evoked by PBSt, suggesting the presence of activity-dependent plasticity of PAD pathways activated by flexor muscle group I afferents. C_LI

neuroscience↗

bioRxiv2020

Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic SCI

After spinal cord injury (SCI), the majority of individuals develop spasticity, a debilitating condition involving involuntary movements, co-contraction of antagonistic muscles, and hyperreflexia. By acting on GABAergic and Ca2+-dependent signaling, current anti-spastic medications lead to serious side effects, including a drastic decrease in motoneuronal excitability which impairs motor function and rehabilitation efforts. Exercise, in contrast, decreases spastic symptoms without decreasing motoneuron excitability. These functional improvements coincide with an increase in expression of the chloride co-transporter KCC2 in lumbar motoneurons. Thus, we hypothesized that spastic symptoms can be alleviated directly through restoration of chloride homeostasis and endogenous inhibition by increasing KCC2 activity. Here, we used the recently developed KCC2 enhancer, CLP257, to evaluate the effects of acutely increasing KCC2 extrusion capability on spastic symptoms after chronic SCI. Sprague Dawley rats received a spinal cord transection at T12 and were either bike-trained or remained sedentary for 5 weeks. Increasing KCC2 activity in the lumbar enlargement improved the rate-dependent depression of the H-reflex and reduced both phasic and tonic EMG responses to muscle stretch in sedentary animals after chronic SCI. Furthermore, the improvements due to this pharmacological treatment mirror those of exercise. Together, our results suggest that pharmacologically increasing KCC2 activity is a promising approach to decrease spastic symptoms in individuals with SCI. By acting to directly to restore endogenous inhibition, this strategy has potential to avoid severe side effects and improve the quality of life of affected individuals. Significance StatementSpasticity is a condition that develops after spinal cord injury (SCI) and causes major complications for individuals. We have previously reported that exercise attenuates spastic symptoms after SCI through an increase in expression of the chloride co-transporter KCC2, suggesting that restoring chloride homeostasis contributes to alleviating spasticity. However, the early implementation of rehabilitation programs in the clinic is often problematic due to co-morbidities. Here, we demonstrate that pharmacologically enhancing KCC2 activity after chronic SCI reduces multiple signs of spasticity, without the need for rehabilitation.

neuroscience↗

bioRxiv2018

Exercise restores chloride homeostasis and decreases spasticity through the BDNF-KCC2 pathway after chronic SCI

Activity-based therapies are routinely integrated in rehabilitation programs to induce repetitive activation of the neuromuscular system and facilitate functional recovery after spinal cord injury (SCI). Among the beneficial effects of physical therapy is a reduction of hyperreflexia and spasticity in SCI individuals, but the precise mechanism by which exercise regulates spinal networks and facilitate recovery remains elusive. Spasticity is a debilitating condition that affects ~ 75% of the SCI population and interferes with residual motor function. Current pharmacological treatments not only have serious side effects but also actively depress spinal excitability and interferes with motor recovery. Understanding how activity-based therapies contribute to decrease spasticity will help identify critical pharmacological targets and optimize rehabilitation programs.\n\nKCC2, a neuron-specific Cl- extruder, is critical to the maintenance of [Cl-]i and its downregulation after SCI leads to a shift in chloride homeostasis that contributes to develop spasticity. We have shown in earlier studies that not only exercise promotes reflex modulation but also restores KCC2 expression in motoneurons. KCC2 is dynamically modulated by several signaling pathways, the most prevalent being BDNF-TrkB. Interestingly, activity-dependent processes triggered by exercise include an increase in the expression of BDNF in the lumbar spinal cord. However, whether the increase in KCC2 contributes to functional recovery and rely on BDNF activity have not been established. Our objective was to determine 1) whether the activity-dependent upregulation of KCC2 contributes to decrease spasticity after SCI; 2) if BDNF regulates KCC2 expression in an activity-dependent manner.\n\nUsing a model of complete SCI, we investigated this possible causal effect by intrathecally delivering VU0240551, a specific KCC2 blocker, or TrkB-IgG, a BDNF scavenger. Drugs were specifically delivered during the daily rehabilitation sessions to transiently prevent KCC2/BDNF activity. We provide evidence that the beneficial effect of exercise on functional recovery relies on a BDNF-dependent increase in KCC2 expression on motoneurons and the restoration of endogenous inhibition to a mature state. We identify, for the first time, that the increase in KCC2 activity with activity-based therapies functionally contributes to H-reflex recovery and critically depends on BDNF activity. This provides a new perspective on our understanding of how exercise impact hyperreflexia by identifying the biological basis of recovery of function. Acting directly on chloride homeostasis through BDNF to restore endogenous inhibition rather than actively depress excitability can diminish the reduction in motor output associated with the current pharmacological management of SCI and improve the outcome of rehabilitation programs.

neuroscience↗