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BMPR1a and BMPR1b signaling exert opposing effects on gliosis after spinal cord injury.

ABSTRACT: Astrogliosis following spinal cord injury (SCI) involves an early hypertrophic response that is beneficial and a subsequent formation of a dense scar. We investigated the role of bone morphogenetic protein (BMP) signaling in gliosis after SCI and find that BMPR1a and BMPR1b signaling exerts opposing effects on hypertrophy. Conditional ablation of BMPR1a from glial fibrillary acidic protein (GFAP)-expressing cells leads to defective astrocytic hypertrophy, increased infiltration by inflammatory cells, and reduced axon density. BMPR1b-null mice conversely develop "hyperactive" reactive astrocytes and consequently have smaller lesion volumes. The effects of ablation of either receptor are reversed in the double knock-out animals. These findings indicate that BMPR1a and BMPR1b exert directly opposing effects on the initial reactive astrocytic hypertrophy. Also, BMPR1b knock-out mice have an attenuated glial scar in the chronic stages following injury, suggesting that it has a greater role in glial scar progression. To elucidate the differing roles of the two receptors in astrocytes, we examined the effects of ablation of either receptor in serum-derived astrocytes in vitro. We find that the two receptors exert opposing effects on the posttranscriptional regulation of astrocytic microRNA-21. Further, overexpression of microRNA-21 in wild-type serum-derived astrocytes causes a dramatic reduction in cell size accompanied by reduction in GFAP levels. Hence, regulation of microRNA-21 by BMP signaling provides a novel mechanism for regulation of astrocytic size. Targeting specific BMPR subunits for therapeutic purposes may thus provide an approach for manipulating gliosis and enhancing functional outcomes after SCI.

SUBMITTER: Sahni V

PROVIDER: S-EPMC3093918 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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BMPR1a and BMPR1b signaling exert opposing effects on gliosis after spinal cord injury.

Sahni Vibhu V Mukhopadhyay Abhishek A Tysseling Vicki V Hebert Amy A Birch Derin D Mcguire Tammy L TL Stupp Samuel I SI Kessler John A JA

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100201 5

Astrogliosis following spinal cord injury (SCI) involves an early hypertrophic response that is beneficial and a subsequent formation of a dense scar. We investigated the role of bone morphogenetic protein (BMP) signaling in gliosis after SCI and find that BMPR1a and BMPR1b signaling exerts opposing effects on hypertrophy. Conditional ablation of BMPR1a from glial fibrillary acidic protein (GFAP)-expressing cells leads to defective astrocytic hypertrophy, increased infiltration by inflammatory c ...[more]

PMID: 20130193

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Project description:Spinal cord injury (SCI) is a debilitating condition with neurological deficits and loss of motor function that, depending on the severity, may lead to paralysis. The only treatment currently available is methylprednisolone, which is widely used and renders limited efficacy in SCI. Therefore, other therapeutic agents must be developed. The neuroprotective efficacy of estrogen in SCI was studied with a pre-clinical and pro-translational perspective. Acute SCI was induced in rats that were treated with low doses of estrogen (1, 5, 10, or 100 μg/kg) and compared with vehicle-treated injured rats or laminectomy control (sham) rats at 48 h post-SCI. Changes in gliosis and other pro-inflammatory responses, expression and activity of proteolytic enzymes (e.g., calpain, caspase-3), apoptosis of neurons in SCI, and cell death were monitored via Western blotting and immunohistochemistry. Negligible pro-inflammatory responses or proteolytic events and very low levels of neuronal death were found in sham rats. In contrast, vehicle-treated SCI rats showed profound pro-inflammatory responses with reactive gliosis, elevated expression and activity of calpain and caspase-3, elevated Bax:Bcl-2 ratio, and high levels of neuronal death in lesion and caudal regions of the injured spinal cord. Estrogen treatment at each dose reduced pro-inflammatory and proteolytic activities and protected neurons in the caudal penumbra in acute SCI. Estrogen treatment at 10 μg was found to be as effective as 100 μg in ameliorating the above parameters in injured animals. Results from this investigation indicated that estrogen at a low dose could be a promising therapeutic agent for treating acute SCI. Experimental studies with low dose estrogen therapy in acute spinal cord injury (SCI) demonstrated the potential for multi-active beneficial outcomes. Estrogen has been found to ameliorate several degenerative pathways following SCI. Thus, such early protective effects may even lead to functional recovery in long term injury. Studies are underway in chronic SCI in a follow up manuscript.

Project description:BACKGROUND: Glial cells are involved in the synaptic elimination process that follows neuronal lesions, and are also responsible for mediating the interaction between the nervous and immune systems. Neurons and glial cells express Toll-like receptors (TLRs), which may affect the plasticity of the central nervous system (CNS). Because TLRs might also have non-immune functions in spinal-cord injury (SCI), we aimed to investigate the influence of TLR2 and TLR4 on synaptic plasticity and glial reactivity after peripheral nerve axotomy. METHODS: The lumbar spinal cords of C3H/HePas wild-type (WT) mice, C3H/HeJ TLR4-mutant mice, C57BL/6J WT mice, and C57BL/6J TLR2 knockout (KO) mice were studied after unilateral sciatic nerve transection. The mice were killed via intracardiac perfusion, and the spinal cord was processed for immunohistochemistry, transmission electron microscopy (TEM), western blotting, cell culture, and reverse transcriptase PCR. Primary cultures of astrocytes from newborn mice were established to study the astrocyte response in the absence of TLR2 and the deficiency of TLR4 expression. RESULTS: The results showed that TLR4 and TLR2 expression in the CNS may have opposite effects on the stability of presynaptic terminals in the spinal cord. First, TLR4 contributed to synaptic preservation of terminals in apposition to lesioned motor neurons after peripheral injury, regardless of major histocompatibility complex class I (MHC I) expression. In addition, in the presence of TLR4, there was upregulation of glial cell-derived neurotrophic factor and downregulation of interleukin-6, but no morphological differences in glial reactivity were seen. By contrast, TLR2 expression led to greater synaptic loss, correlating with increased astrogliosis and upregulation of pro-inflammatory interleukins. Moreover, the absence of TLR2 resulted in the upregulation of neurotrophic factors and MHC I expression. CONCLUSION: TLR4 and TLR2 in the CNS may have opposite effects on the stability of presynaptic terminals in the spinal cord and in astroglial reactions, indicating possible roles for these proteins in neuronal and glial responses to injury.

Project description:Deficient ankle control after incomplete spinal cord injury (iSCI) often accentuates walking impairments. Transcutaneous electrical spinal cord stimulation (tSCS) has been shown to augment locomotor activity after iSCI, presumably due to modulation of spinal excitability. However, the effects of possible excitability modulations induced by tSCS on ankle control have not yet been assessed. This study investigated the immediate (i.e., without training) effects during single-sessions of tonic tSCS on ankle control, spinal excitability, and locomotion in ten individuals with chronic, sensorimotor iSCI (American Spinal Injury Association Impairment Scale D). Participants performed rhythmic ankle movements (dorsi- and plantar flexion) at a given rate, and irregular ankle movements following a predetermined trajectory with and without tonic tSCS at 15 Hz, 30 Hz, and 50 Hz. In a subgroup of eight participants, the effects of tSCS on assisted over-ground walking were studied. Furthermore, the activity of a polysynaptic spinal reflex, associated with spinal locomotor networks, was investigated to study the effect of the stimulation on the dedicated spinal circuitry associated with locomotor function. Tonic tSCS at 30 Hz immediately improved maximum dorsiflexion by +4.6° ± 0.9° in the more affected lower limb during the rhythmic ankle movement task, resulting in an increase of +2.9° ± 0.9° in active range of motion. Coordination of ankle movements, assessed by the ability to perform rhythmic ankle movements at a given target rate and to perform irregular movements according to a trajectory, was unchanged during stimulation. tSCS at 30 Hz modulated spinal reflex activity, reflected by a significant suppression of pathological activity specific to SCI in the assessed polysynaptic spinal reflex. During walking, there was no statistical group effect of tSCS. In the subgroup of eight assessed participants, the three with the lowest as well as the one with the highest walking function scores showed positive stimulation effects, including increased maximum walking speed, or more continuous and faster stepping at a self-selected speed. Future studies need to investigate if multiple applications and individual optimization of the stimulation parameters can increase the effects of tSCS, and if the technique can improve the outcome of locomotor rehabilitation after iSCI.

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BMPR1a and BMPR1b signaling exert opposing effects on gliosis after spinal cord injury.

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BMPR1a and BMPR1b signaling exert opposing effects on gliosis after spinal cord injury.

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