C57BL/6 and Swiss Webster Mice Display Differences in Mobility, Gliosis, Microcavity Formation and Lesion Volume After Severe Spinal Cord Injury

Spinal cord injuries (SCI) are neuropathologies causing enormous physical and emotional anguish as well as irreversibly disabilities with great socio/economic burdens to our society. The availability of multiple mouse strains is important for studying the underlying pathophysiological response after SCI. Although strain differences have been shown to directly affect spontaneous functional recovery following incomplete SCI, its influence after complete lesion of the spinal cord is unclear. To study the influence of mouse strain on recovery after severe SCI, we first carried out behavioral analyses up to 6 weeks following complete transection of the spinal cord in mice with two different genetic backgrounds namely, C57BL/6 and Swiss Webster. Using immunohistochemistry, we then analyzed glial cell reactivity not only at different time-points after injury but also at different distances from the lesion epicenter. Behavioral assessments using CatWalk™ and open field analyses revealed increased mobility (measured using average speed) and differential forelimb gross sensory response in Swiss Webster compared to C57BL/6 mice after complete transection of the spinal cord. Comprehensive histological assessment revealed elevated microglia/macrophage reactivity and a moderate increase in astrogliosis in Swiss Webster that was associated with reduced microcavity formation and reduced lesion volume after spinal cord transection compared to C57BL/6 mice. Our results thus suggest that increased mobility correlates with enhanced gliosis and better tissue protection after complete transection of the spinal cord

Gacyclidine improves the survival and reduces motor deficits in a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder typified by a massive loss of motor neurons with few therapeutic options. The exact cause of neuronal degeneration is unknown but it is now admitted that ALS is a multifactorial disease with several mechanisms involved including glutamate excitotoxicity. More specifically, N-methyl-D-aspartate (NMDA)-mediated cell death and impairment of the glutamate-transport has been suggested to play a key role in ALS pathophysiology. Thus, evaluating NMDAR antagonists is of high therapeutic interest. Gacyclidine, also named GK11, is a high affinity non-competitive NMDAR antagonist that may protect against motor neuron death in an ALS context. Moreover, GK11 presents a low intrinsic neurotoxicity and has already been used in two clinical trials for CNS lesions. <br/>In the present study, we investigated the influence of chronic administration of two doses of GK11 (0.1 and 1 mg/kg) on the survival and the functional motor activity of hSOD1G93A mice, an animal model of ALS. Treatment started at early symptomatic age (60 days) and was applied bi-weekly until the end stage of the disease. We first confirmed that functional alteration of locomotor activity was evident in the hSOD1G93A transgenic female mice by 60 days of age. A low dose of GK11 improved the survival of the mice by 4.3% and partially preserved body weight. Improved life span was associated with a delay in locomotor function impairment. Conversely, the high dose treatment worsened motor functions. <br/>These findings suggest that chronic administration of GK11beginning at early symptomatic stage may be beneficial for patients with ALS

Serotonergic Mechanisms in Spinal Cord Injury

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Astrocyte-to-neuron conversion induced by spinal cord injury

International audienceSpinal cord injury (SCI) triggers pronounced astrocyte reactivity (astrogliosis) including astroglial proliferation and migration toward the injury site participating to the formation of a glial scar. Since the mid-20 th century, SCI-induced astrogliosis was mainly regarded as detrimental for successful axonal regeneration. However, more recent studies have shown astrogliosis as a multifactorial phenomenon involving specific morphological, molecular and functional alterations in astrocytes that can also exert beneficial effects [1, 2]. It was suggested, although not proven, that SCI-induced astrogliosis depends on multiple factors such as time after lesion, injury severity and distance to the lesion site. In a recent study we had attempted to uncover the molecular involvement of astrocytes after SCI by studying their transcriptomic alterations at different stages after moderate and severe lesions [3]. Aldehyde dehydrogenase 1 family member L1 (Aldh1l1) is a pan-astrocytic marker, hence using the Aldh1l1-EGFP transgenic mice, combined with fluorescence-activated cell sorting (FACS), we isolated pure astrocyte population at different stages following SCI. Choosing lateral hemisection and complete section of the spinal cord, as moderate and severe injury models, we investigated astrocytic response at 1 and 2 weeks after lesion. We subsequently carried out astrocyte-specific RNA-sequencing and pathway analyses to unveil the molecular signature of injuries-induced astrogliosis. Our transcriptomic analyses demonstrated a dual astrocytic response depending on time post-injury and lesion severity. Following moderate SCI, astrocytes displayed a protective role and showed no changes (1 week) and even down-regulated (2 weeks) expression of transcripts involved in immune response. On the other hand, astrocytes response after severe SCI seems to be detrimental by an upsurge expression of inflammatory genes (1 week) and prevention of extracellular re-modeling (2 weeks) (3). These are the first concrete evidence of a heterogeneous astrocytic response that is driven not only by lesion severity but also time after injury (Figure 1). In parallel, using pathway analyses, we also identified in astrocytes the induction of the neural stem cell lineage and the over-expression of the neuronal progenitor gene βIII-tubulin (Tubb3, also known as TUJ1). We confirmed βIII-tubulin protein expression at tissue level using immunohistochemistry and at single cell level using FACS analyses. The sub-population of astrocytes that express βIII-tubulin was only found within 750µm distance to the lesion epicenter. Astrocytes co-expressing βIII-tubulin, also displayed alterations in their morphology from typical stellate shape to classical neuronal progenitor cells with bipolar or multipolar processes. Given that SCI induces astrocytic proliferation, we injected BrdU in Aldh1l1-EGFP mice after injury to determine the origin of eGFP/βIII-tubulin co-expressing cells. BrdU incorporation was observed into newly formed astrocytes but not in eGFP/βIII-tubulin-expressing astrocytes. This suggests that it is the resident mature astrocytes, rather than newly formed astrocytes, that undergo transdifferentiation towards neuronal lineage (Figure 1). Time-dependent analyses revealed that astrocytic conversion towards neuronal lineage starts as early as 72 hours, peaking between 1-2 weeks and continues to a lower degree up to 6 weeks after both moderate and severe SCI. Further immunostaining, using mature neuronal markers, showed that transdifferentiating astrocytes eventually express GABAergic, but not glutamatergic, markers. Moreover, we identified the fibroblast growth factor receptor 4 (Fgfr4) as a potential player responsible for SCI-induced astrocytic transdifferentiation towards neuronal lineage. Fgfr4 indeed promotes embryonic stem cell differentiation towards neuronal lineage [4] and showed pronounced over-expression from 72 hours following lesion at both RNA and protein level. Although other recent studies had shown limited astrocytes conversion towards neuronal lineage upon enforced expression of neurogenic factors, none had Editorial Figure 1: Schematic cartoon displaying summary of astrocytic responses following SC

Diving-induced cervical spine injuries: a 10-year retrospective descriptive study

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Motoneuron Resistance to Apoptotic Cell Death In Vivo Correlates with the Ratio between X-Linked Inhibitor of Apoptosis Proteins (XIAPs) and Its Inhibitor, XIAP-Associated Factor 1

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Repair strategies and functional restoration of the injured spinal cord

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Image_2_C57BL/6 and Swiss Webster Mice Display Differences in Mobility, Gliosis, Microcavity Formation and Lesion Volume After Severe Spinal Cord Injury.TIF

<p>Spinal cord injuries (SCI) are neuropathologies causing enormous physical and emotional anguish as well as irreversibly disabilities with great socio/economic burdens to our society. The availability of multiple mouse strains is important for studying the underlying pathophysiological response after SCI. Although strain differences have been shown to directly affect spontaneous functional recovery following incomplete SCI, its influence after complete lesion of the spinal cord is unclear. To study the influence of mouse strain on recovery after severe SCI, we first carried out behavioral analyses up to 6 weeks following complete transection of the spinal cord in mice with two different genetic backgrounds namely, C57BL/6 and Swiss Webster. Using immunohistochemistry, we then analyzed glial cell reactivity not only at different time-points after injury but also at different distances from the lesion epicenter. Behavioral assessments using CatWalk™ and open field analyses revealed increased mobility (measured using average speed) and differential forelimb gross sensory response in Swiss Webster compared to C57BL/6 mice after complete transection of the spinal cord. Comprehensive histological assessment revealed elevated microglia/macrophage reactivity and a moderate increase in astrogliosis in Swiss Webster that was associated with reduced microcavity formation and reduced lesion volume after spinal cord transection compared to C57BL/6 mice. Our results thus suggest that increased mobility correlates with enhanced gliosis and better tissue protection after complete transection of the spinal cord.</p