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Spinal cord injury (SCI) results in the development of detrimental autoantibodies against the lesioned spinal cord. IgM immunoglobulin maintains homeostasis against IgG-autoantibody responses, but its effect on SCI recovery remains unknown. In the present study we investigated the role of IgM immunoglobulin in influencing recovery after SCI. To this end, we induced cervical SCI at the C6/C7 level in mice that lacked secreted IgM immunoglobulin (IgM-KO) and their wild type (WT) littermate controls. Overall, the absence of secretory IgM resulted in worse outcomes as compared to WT mice with SCI. At two weeks post injury, IgM knock-out (KO) mice had significantly more IgG antibodies, which fixed the complement system, in the injured spinal cord parenchyma. In addition to these findings, IgM-KO mice had more parenchymal T-lymphocytes as well as CD11b+ microglia/macrophages, which co-localized with myelin. At 10 weeks post-injury, IgM-KO mice showed significant impairment in neurobehavioral recovery, such as deteriorated coordination, reduced hindlimb swing speed and print area. These neurobehavioral detriments were coupled with increased lesional tissue and myelin loss. Taken together, this study provides the first evidence for the importance of IgM immunoglobulin in modulating recovery after SCI and suggests that modulating IgM could be a novel therapeutic approach to enhance recovery after SCI. Significance statement The present study provides novel evidence for the protective role of IgM immunoglobulin in SCI. Using a clinically relevant mouse model of SCI at the cervical level (C6/C7), we show that deficiency of IgM immunoglobulin results in impaired neurobehavioral recovery, coupled with increased lesion size, less white matter sparing, and enhanced deposition of complement-fixing IgG antibodies in the spinal cord. These data provide evidence for the necessary role of IgM immunoglobulin in spontaneous recovery during cervical SCI and warrant more research into the therapeutic effect of IgM administration after SCI.

Cervical spinal cord injury (cSCI) occurs in over half of all cases of traumatic spinal cord injury (SCI), yet we lack therapies that can generate significant functional recovery in these patients. The development of animal models of cSCI will aid in the pre-clinical assessment of therapies and in understanding basic pathophysiological mechanisms. Here, we describe a clinically relevant model of cervical contusion-compression injury in the mouse. Using a modified aneurysm clip, we generated a bilateral, incomplete injury that mimics contusion-compression injuries most commonly observed in humans. We followed the recovery of injured and sham-operated (laminectomy-only) animals for 8 weeks post-surgery. Behavioral tests, including the Basso Mouse Scale (BMS), wire hanging, grip strength, and CatWalk automated gait analysis, showed that while natural recovery is limited, it occurs in a clinically relevant window during the subacute phase of injury (7-14 days post-SCI). BMS scoring demonstrated that, while injured animals are ambulatory, they do not recover normal locomotor ability. CatWalk analysis quantitatively showed a loss of coordination and motor ability, with minimal recovery. The wire hanging and grip strength tests confirmed a significant decrease in forelimb motor strength in injured animals. Histological analysis carried out during the subacute phase (7-day time point) and chronic phase (8-week time point) demonstrated that the lesion epicenter is formed by 7 days post-SCI. Volumetric analysis of protein kinase C gamma (PKCgamma)-stained axons revealed that this injury results in significant damage to the corticospinal tract caudal to the injury site. Finally, we used quantitative real-time polymerase chain reaction to show that genes associated with inflammation and glial scarring are upregulated as a result of injury. This study confirms that we can effectively model bilateral cervical injury in the mouse and provides a framework for future studies using this model to assess therapies.

Despite the increasing incidence and prevalence of cervical spinal cord injury (cSCI), we lack clinically relevant animal models that can be used to study the pathomechanisms of this injury and test new therapies. Here, we characterize a moderate cervical contusion-compression model in rats that is similar to incomplete traumatic cSCI in humans. We characterized the effects of 18-g clip-compression injury at cervical level C6 over an 8-week recovery period. Using Luxol fast blue/hematoxylin-eosin staining in combination with quantitative stereology, we determined that 18-g injury results in loss of gray matter (GM), white matter (WM), as well as in cavity formation. Magnetization transfer and T2-weighted magnetic resonance imaging were used to analyze lesion dynamics in vivo. This analysis demonstrated that both techniques are able to differentiate between the injury epicenter, subpial rim, and WM distal to the injury. Neurobehavioral assessment of locomotor function using Basso, Beattie, and Bresnahan (BBB) scoring and CatWalk revealed limited recovery from clip-compression injury at C6. Testing of forelimb function using grip strength demonstrated significant forelimb dysfunction, similar to the loss of upper-limb motor function observed in human cSCI. Sensory-evoked potentials recorded from the forelimb and Hoffman reflex recorded from the hindlimb confirmed the fore- and hindlimb deficits observed in our neurobehavioral analysis. Here, we have characterized a clip-compression model of incomplete cSCI that closely models this condition in humans. This work directly addresses the current lack of clinically relevant models of cSCI and will thus contribute to improved success in the translation of putative therapies into the clinic.

Background The Rho pathway has been shown to have a role in the pathophysiology of spinal cord injury (SCI). Upregulation of the Rho signaling pathway occurs as a result of SCI. Activation of Rho and its downstream effector kinases triggers growth cone collapse and represents a significant barrier to axon regeneration. Furthermore, there is evidence that Rho-ROCK signaling mediates the inhibitory effects of chondroitin sulfate proteoglycans on neurons, and that inhibition of Rho and ROCK can reverse chondroitin sulfate proteoglycan-mediated inhibition of neurite outgrowth. Work building on these findings suggests that inhibition of this pathway may boost neuroprotection and axonal regeneration after SCI. Methods A narrative review. Results Investigators have identified a C3 transferase, which selectively inhibits Rho without affecting other guanine triphosphatases. This has been shown to promote axonal sprouting and recovery of locomotor function after hemisection of the thoracic spinal cord in a mouse model of SCI. The neuroprotective properties of Rho inhibitors in animal models of SCI have been reinforced by studies carried out in vitro using retinal ganglion cells. In light of this, a Rho inhibitor known as Cethrin has been evaluated as a therapeutic intervention for SCI in a phase I/IIa clinical trial with promising results. Conclusions The Rho pathway has been shown to have a role in the pathophysiology of SCI and preclinical and clinical work and is currently a promising target for the treatment of patients with SCI.

Inhibition of histone deacetylase (HDAC) activity results in dedifferentiation of various neural precursor cell populations, but is also known to promote neuronal differentiation. We sought to determine the effects of HDAC inhibition on differentiated and non-differentiated midbrain cells in order to examine more closely the consequences of HDAC inhibition on cell fate in a heterogeneous population. We demonstrate that HDAC inhibitor (HDACi) treatment causes a significant attenuation in the numbers of neurons, but not astrocytes, within 48 h, with no evidence of neuronal dedifferentiation. The loss of neurons is due to an initial morphological destabilization, which is not recoverable upon inhibitor removal, and ultimately leads to cell death. HDACi treatment results in progenitor cell cycle arrest and Caspase-dependent apoptosis. In contrast, the loss of midbrain neurons does not correlate with activated Caspase-3 expression. Treating cultures transiently with Caspase inhibitors blocks overall HDACi-induced cell death in the cultures, but does not prevent the loss of neurons. These data suggest that HDACi treated midbrain neurons undergo Caspase-independent cell death. Finally, we demonstrate that cortical neurons do not undergo cell death in response to HDACi treatment, suggesting that there may be tissue-specific or microenvironmental factors that promote the susceptibility of midbrain neurons to the neurotoxic effects of HDAC inhibition.

Human male infertility affects ∼5% of men, with one-third suffering from testicular failure, likely the result of an underlying genetic abnormality that disrupts spermatogenesis during development. Mouse models of male infertility such as thePpp1ccknockout mouse display very similar phenotypes to humans with testicular failure. MalePpp1ccmutant mice are sterile due to disruptions in spermatogenesis that begin during prepubertal testicular development, and continue into adulthood, often resulting in loss of germ cells to the point of Sertoli cell-only syndrome. The current study employs light and electron microscopy to identify new morphological abnormalities inPpp1ccmutant seminiferous epithelium. This study reveals that germ cells become delayed in their development around stages VII and VIII of spermatogenesis. Loss of these cells likely results in the reduced numbers of elongating spermatids and spermatozoa previously observed in mutant animals. Interestingly,Ppp1ccmutants also display reduced numbers of spermatogonia compared with their wild-type counterparts. Using electron microscopy, we have shown that junction complexes inPpp1ccmutants are ultrastructurally normal, and therefore do not contribute to the breakdown in tissue architecture seen in mutants. Electron microscopy revealed major acrosomal and chromatin condensation defects inPpp1ccmutants. Our observations are discussed in the context of known molecular changes inPpp1ccmutant testes.

Spinal cord injuries (SCI) cause serious neurological impairment and psychological, economic, and social consequences for patients and their families. Clinically, more than 50% of SCI affect the cervical spine1. As a consequence of the primary injury, a cascade of secondary mechanisms including inflammation, apoptosis, and demyelination occur finally leading to tissue scarring and development of intramedullary cavities2,3. Both represent physical and chemical barriers to cell transplantation, integration, and regeneration. Therefore, shaping the inhibitory environment and bridging cavities to create a supportive milieu for cell transplantation and regeneration is a promising therapeutic target4. Here, a contusion/compression model of cervical SCI using an aneurysm clip is described. This model is more clinically relevant than other experimental models, since complete transection or ruptures of the cord are rare. Also in comparison to the weight drop model, which in particular damage the dorsum columns, circumferential compression of the spinal cord appears advantageous. Clip closing force and duration can be adjusted to achieve different injury severity. A ring spring facilitates precise calibration and constancy of clip force. Under physiological conditions, synthetic self-assembling peptides (SAP) self-assemble into nanofibers and thus, are appealing for application in SCI5. They can be injected directly into the lesion minimizing damage to the cord. SAPs are biocompatible structures erecting scaffolds to bridge intramedullary cavities and thus, equip the damaged cord for regenerative treatments. K2(QL)6K2 (QL6) is a novel SAP introduced by Dong et al.6 In comparison to other peptides, QL6 self-assembles into β-sheets at neutral pH6.14 days after SCI, after the acute stage, SAPs are injected into the center of the lesion and neural precursor cells (NPC) are injected into adjacent dorsal columns. In order to support cell survival, transplantation is combined with continuous subdural administration of growth factors by osmotic micro pumps for 7 days.

The mechanisms by which neural precursor cells (NPCs) enhance functional recovery from spinal cord injury (SCI) remain unclear. Spinal cord injured rats were transplanted with wild-type mouse NPCs, shiverer NPCs unable to produce myelin, dead NPCs, or media. Most animals also received minocycline, cyclosporine, and perilesional infusion of trophins. Motor function was graded according to the BBB scale. H&E/LFB staining was used to assess gray and white matter, cyst, and lesional tissue. Mature oligodendrocytes and ED1+inflammatory cells were quantitated. Confocal and electron microscopy were used to assess the relationship between the transplanted cells and axons. Pharmacotherapy and trophin infusion preserved gray matter, white matter, and oligodendrocytes. Trophin infusion also significantly increased cyst and lesional tissue volume as well as inflammatory infiltrate, and functional recovery was reduced. Animals transplanted with wild-type NPCs showed greatest functional recovery; animals transplanted with shiverer NPCs performed the worst. Wild-type NPCs remyelinated host axons. Shiverer NPCs ensheathed axons but did not produce MBP. These results suggest that remyelination by NPCs is an important contribution to functional recovery following SCI. Shiverer NPCs may prevent remyelination by endogenous cells capable of myelin formation. These findings suggest that remyelination is an important therapeutic target following SCI.

There are currently about 85 000 Canadians living with spinal cord injuries, more than half of which are secondary to trauma.[1][1] As the population ages, the incidence and prevalence of traumatic spinal cord injury are expected to increase, primarily as a result of fall-related injuries among