Expressions of VGLUT1/2 in the inspiratory interneurons and GAD65/67 in the inspiratory Renshaw cells in the neonatal rat upper thoracic spinal cord

Iizuka, Makito; Ikeda, Keiko; Onimaru, Hiroshi; Izumizaki, Masahiko

doi:10.1016/j.ibror.2018.08.001

Cited by 5 publications

(8 citation statements)

References 57 publications

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“…VGlut1/2-expressing interneurons in Laminae III–V also control and modulate motor neurons. 61 As such, behavioural improvements after epoB treatment could be attributed to strengthening excitatory networks.…”

Section: Discussionmentioning

confidence: 99%

Rehabilitation enhances epothilone-induced locomotor recovery after spinal cord injury

Griffin

Prakash

Bockemühl

et al. 2022

Brain Communications

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Microtubule stabilisation through epothilones is a promising preclinical therapy for functional recovery following spinal cord injury that stimulates axon regeneration, reduces growth-inhibitory molecule deposition, and promotes functional improvements. Rehabilitation therapy is the only clinically validated approach to promote functional improvements following spinal cord injury. However, whether microtubule stabilization can augment the beneficial effects of rehabilitation therapy or act in concert with it to further promote repair remains unknown. Here, we investigated the pharmacokinetic, histological, and functional efficacies of epothilone D, epothilone B, and ixabepilone alone or in combination with rehabilitation following a moderate contusive spinal cord injury. Pharmacokinetic analysis revealed that ixabepilone only weakly crossed the blood-brain-barrier and was subsequently excluded from further investigations. In contrast, epothilones B and D rapidly distributed to CNS compartments displaying similar profiles after either subcutaneous or intraperitoneal injections. Following injury and subcutaneous administration of epothilone B or D, rats were subjected to seven weeks of sequential bipedal and quadrupedal training. For all outcome measures, epothilone B was efficacious compared to epothilone D. Specifically, epothilone B decreased fibrotic scaring which was associated with a retention of fibronectin localised to perivascular cells in sections distal to the lesion. This corresponded to a decreased number of cells present within the intralesional space resulting in less axons within the lesion. Instead, epothilone B increased serotonergic fiber regeneration and vesicular glutamate transporter 1 expression caudal to the lesion, which was not affected by rehabilitation. Multiparametric behavioural analyses consisting of open field locomotor scoring, horizontal ladder, catwalk gait analysis, and hindlimb kinematics revealed that rehabilitation and epothilone B both improved several aspects of locomotion. Specifically, rehabilitation improved open field locomotor and ladder scores, as well as improving the gait parameters of limb coupling, limb support, stride length and limb speed; epothilone B improved these same gait parameters but also hindlimb kinematic profiles. Functional improvements by epothilone B and rehabilitation acted complementary on gait parameters leading to an enhanced recovery in the combination group. As a result, principal component analysis of gait showed a greatest improvement in the epothilone B plus rehabilitation group. Thus, these results support the combination of epothilone B with rehabilitation in a clinical setting.

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Section: Discussionmentioning

confidence: 99%

Rehabilitation enhances epothilone-induced locomotor recovery after spinal cord injury

Griffin

Prakash

Bockemühl

et al. 2022

Brain Communications

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“…Inspiratory and expiratory neurons are also found in the thoracic cord and it has been estimated that they outnumber bulbospinal respiratory neurons by 10 to 1 (Kirkwood et al, 1988). Both excitatory and inhibitory respiratory neurons have been described (Saywell et al, 2011;Iizuka et al, 2016Iizuka et al, , 2018. Propriospinal neurons that control limb movements, posture, or autonomic functions are also found in the cervical and thoracic cord.…”

Section: Propriospinal Neurons Shape the Pattern Of Respiratory Motormentioning

confidence: 99%

“…Studies of the rat phrenic nucleus have identified inspiratory, expiratory, and tonic firing inhibitory (GABAergic) interneurons (Marchenko et al, 2015;Ghali, 2018). The inspiratory inhibitory neurons include, but are probably not limited to, Renshaw cells that provide recurrent inhibition to phrenic and intercostal motor neurons (Kirkwood et al, 1981;Hilaire et al, 1983Hilaire et al, , 1986Lipski et al, 1985;Iizuka et al, 2018). Blocking GABAergic inhibition by spinal neurons alters the shape of the phrenic motor burst and increases activity during expiration (Marchenko et al, 2015).…”

Section: Propriospinal Neurons Shape the Pattern Of Respiratory Motormentioning

confidence: 99%

“…In locomotor circuits, V1 neurons shape motor bursts to control the duration of stance and swing phases of the step cycle and thus the speed of walking (Gosgnach et al, 2006). Renshaw cells (a subset of V1 neurons) provide recurrent inhibition to phrenic and intercostal motor neurons (Kirkwood et al, 1981;Hilaire et al, 1983Hilaire et al, , 1986Lipski et al, 1985;Iizuka et al, 2018), but the role of most V1 neurons in breathing is unknown. One could hypothesize that the GABAergic neurons that shape respiratory motor bursts (Marchenko et al, 2015) are a subset(s) of V1 neurons.…”

Section: Potential Roles For Developmental Neuron Classes In Breathingmentioning

confidence: 99%

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Role of Propriospinal Neurons in Control of Respiratory Muscles and Recovery of Breathing Following Injury

Jensen

Alilain

Crone

2020

Front. Syst. Neurosci.

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Respiratory motor failure is the leading cause of death in spinal cord injury (SCI). Cervical injuries disrupt connections between brainstem neurons that are the primary source of excitatory drive to respiratory motor neurons in the spinal cord and their targets. In addition to direct connections from bulbospinal neurons, respiratory motor neurons also receive excitatory and inhibitory inputs from propriospinal neurons, yet their role in the control of breathing is often overlooked. In this review, we will present evidence that propriospinal neurons play important roles in patterning muscle activity for breathing. These roles likely include shaping the pattern of respiratory motor output, processing and transmitting sensory afferent information, coordinating ventilation with motor activity, and regulating accessory and respiratory muscle activity. In addition, we discuss recent studies that have highlighted the importance of propriospinal neurons for recovery of respiratory muscle function following SCI. We propose that molecular genetic approaches to target specific developmental neuron classes in the spinal cord would help investigators resolve the many roles of propriospinal neurons in the control of breathing. A better understanding of how spinal circuits pattern breathing could lead to new treatments to improve breathing following injury or disease.

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“…Using a voltage-sensitive dye, we further observed that this blockade of glycine and GABA A receptors increased inspiratory depolarizing signals in the interneuron area of the rostral thoracic spinal cord [ 2 ]. Using whole-cell patch clamp recording and the in situ hybridization method, we also showed that some inspiratory interneurons in the ventromedial portion of the rostral thoracic spinal cord are glutamatergic [ 3 ]. We have thus hypothesized that the enhancement of inspiratory motor activity comes from the enhancement of firing in these active inspiratory interneurons and/or the recruitment of inspiratory interneurons that give excitatory synaptic input to the motoneurons.…”

Section: Introductionmentioning

confidence: 99%

Glycine and GABAA receptors suppressively regulate the inspiratory-related calcium rise in the thoracic inspiratory cells of the neonatal rat

Mikami

Iizuka²,

Onimaru³

et al. 2022

J Physiol Sci

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We previously demonstrated that in an isolated brainstem–spinal cord preparation from neonatal rats, a local bath application of strychnine (a broad antagonist of glycine and GABAA receptors) to the spinal cord enhances thoracic inspiratory motor activity. Herein, to investigate the involvement of the inspiratory spinal interneurons that provide excitatory input to the motoneuron, we conducted calcium imaging using this preparation. Oregon Green 488 BAPTA-1 AM, a fluorescent calcium indicator, was injected into the ventromedial surface of the thoracic cord. In all cells that showed inspiratory-related fluorescence changes > 2% of the baseline fluorescence intensity, the inspiratory-related fluorescence change decreased when the focal depth was deepened. The application of strychnine to the spinal cord increased the inspiratory-related intracellular calcium rise in these cells. These results suggest that the enhancement of inspiratory interneuron activity could be involved in this enhancement of inspiratory motor activity.

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Expressions of VGLUT1/2 in the inspiratory interneurons and GAD65/67 in the inspiratory Renshaw cells in the neonatal rat upper thoracic spinal cord

Cited by 5 publications

References 57 publications

Rehabilitation enhances epothilone-induced locomotor recovery after spinal cord injury

Rehabilitation enhances epothilone-induced locomotor recovery after spinal cord injury

Role of Propriospinal Neurons in Control of Respiratory Muscles and Recovery of Breathing Following Injury

Glycine and GABAA receptors suppressively regulate the inspiratory-related calcium rise in the thoracic inspiratory cells of the neonatal rat

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