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Astrocyte matricellular proteins that control excitatory synaptogenesis are regulated by inflammatory cytokines and correlate with paralysis severity during experimental autoimmune encephalomyelitis.

Blakely PK, Hussain S, Carlin LE, Irani DN - Front Neurosci (2015)

Bottom Line: Taken together, these data support a model whereby proinflammatory cytokines inhibit SPARCL1 and/or augment SPARC expression by astrocytes in spinal gray matter that, in turn, cause either transient or sustained synaptic retraction from lumbar spinal motor neurons thereby regulating hind limb paralysis during EAE.Ongoing studies seek ways to alter this SPARCL1:SPARC expression ratio in favor of synapse reformation/maintenance and thus help to modulate neurologic deficits during times of inflammation.This could identify new astrocyte-targeted therapies for diseases such as multiple sclerosis.

View Article: PubMed Central - PubMed

Affiliation: Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan Medical School Ann Arbor, MI, USA.

ABSTRACT
The matricellular proteins, secreted protein acidic and rich in cysteine (SPARC) and SPARC-like 1 (SPARCL1), are produced by astrocytes and control excitatory synaptogenesis in the central nervous system. While SPARCL1 directly promotes excitatory synapse formation in vitro and in the developing nervous system in vivo, SPARC specifically antagonizes the synaptogenic actions of SPARCL1. We hypothesized these proteins also help maintain existing excitatory synapses in adult hosts, and that local inflammation in the spinal cord alters their production in a way that dynamically modulates motor synapses and impacts the severity of paralysis during experimental autoimmune encephalomyelitis (EAE) in mice. Using a spontaneously remitting EAE model, paralysis severity correlated inversely with both expression of synaptic proteins and the number of synapses in direct contact with the perikarya of motor neurons in spinal gray matter. In both remitting and non-remitting EAE models, paralysis severity also correlated inversely with sparcl1:sparc transcript and SPARCL1:SPARC protein ratios directly in lumbar spinal cord tissue. In vitro, astrocyte production of both SPARCL1 and SPARC was regulated by T cell-derived cytokines, causing dynamic modulation of the SPARCL1:SPARC expression ratio. Taken together, these data support a model whereby proinflammatory cytokines inhibit SPARCL1 and/or augment SPARC expression by astrocytes in spinal gray matter that, in turn, cause either transient or sustained synaptic retraction from lumbar spinal motor neurons thereby regulating hind limb paralysis during EAE. Ongoing studies seek ways to alter this SPARCL1:SPARC expression ratio in favor of synapse reformation/maintenance and thus help to modulate neurologic deficits during times of inflammation. This could identify new astrocyte-targeted therapies for diseases such as multiple sclerosis.

No MeSH data available.


Related in: MedlinePlus

Expression of synaptic proteins in lumbar spinal gray matter is dynamically regulated during relapsing EAE. (A) Representative immunohistochemical staining for the presynaptic protein, synaptophysin, and the postsynaptic protein, MAP2, shows that both proteins localize to lumbar spinal gray matter at varying stages of relapsing EAE in SJL mice. Inserts show that synaptophysin labels gray matter neuropil while MAP2 labels neuronal cell bodies and proximal dendrites. (B) Normalized expression of both proteins shows reduced levels at peak disease, but notable recovery by the time of disease remission only a few days later (n = 5 samples per disease stage). Bar = 80 μm, *p < 0.05 compared to preclinical levels.
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Figure 2: Expression of synaptic proteins in lumbar spinal gray matter is dynamically regulated during relapsing EAE. (A) Representative immunohistochemical staining for the presynaptic protein, synaptophysin, and the postsynaptic protein, MAP2, shows that both proteins localize to lumbar spinal gray matter at varying stages of relapsing EAE in SJL mice. Inserts show that synaptophysin labels gray matter neuropil while MAP2 labels neuronal cell bodies and proximal dendrites. (B) Normalized expression of both proteins shows reduced levels at peak disease, but notable recovery by the time of disease remission only a few days later (n = 5 samples per disease stage). Bar = 80 μm, *p < 0.05 compared to preclinical levels.

Mentions: To survey the general integrity of synapses in the lumbar spinal cords of mice with relapsing EAE, tissue expression of the pre-synaptic neuronal protein, synaptophysin, and the post-synaptic neuronal protein, MAP2, were assessed. By immunohistochemistry both proteins localized exclusively to spinal gray matter (Figure 2A), and by Western blot both proteins were dynamically regulated in directions opposite to paralysis severity (i.e., levels declined as paralysis scores increased, and vice versa) (Figure 2B). Focusing on the motor pathway at an ultrastructural level, the actual number of synapses found in direct contact with the perikarya of lumbar spinal motor neurons were notably reduced at peak disease but recovered as motor function returned back to normal (Figures 3A,B). At peak disease, few of these axosomatic synapses showed evidence that another cell had interposed a process between itself and the neuronal cell body; most appeared to have simply retracted from the cell perimeter (Figures 3C,D). Together, these data suggest that physical changes to the synapses projecting directly onto ventral motor neurons or their dendritic processes could contribute to the fluctuating paralysis that typifies relapsing-remitting EAE. They also show that dynamic modulation of these synaptic connections occurs in both temporal and spatial proximity to reactive astrocytes in surrounding gray matter.


Astrocyte matricellular proteins that control excitatory synaptogenesis are regulated by inflammatory cytokines and correlate with paralysis severity during experimental autoimmune encephalomyelitis.

Blakely PK, Hussain S, Carlin LE, Irani DN - Front Neurosci (2015)

Expression of synaptic proteins in lumbar spinal gray matter is dynamically regulated during relapsing EAE. (A) Representative immunohistochemical staining for the presynaptic protein, synaptophysin, and the postsynaptic protein, MAP2, shows that both proteins localize to lumbar spinal gray matter at varying stages of relapsing EAE in SJL mice. Inserts show that synaptophysin labels gray matter neuropil while MAP2 labels neuronal cell bodies and proximal dendrites. (B) Normalized expression of both proteins shows reduced levels at peak disease, but notable recovery by the time of disease remission only a few days later (n = 5 samples per disease stage). Bar = 80 μm, *p < 0.05 compared to preclinical levels.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4598482&req=5

Figure 2: Expression of synaptic proteins in lumbar spinal gray matter is dynamically regulated during relapsing EAE. (A) Representative immunohistochemical staining for the presynaptic protein, synaptophysin, and the postsynaptic protein, MAP2, shows that both proteins localize to lumbar spinal gray matter at varying stages of relapsing EAE in SJL mice. Inserts show that synaptophysin labels gray matter neuropil while MAP2 labels neuronal cell bodies and proximal dendrites. (B) Normalized expression of both proteins shows reduced levels at peak disease, but notable recovery by the time of disease remission only a few days later (n = 5 samples per disease stage). Bar = 80 μm, *p < 0.05 compared to preclinical levels.
Mentions: To survey the general integrity of synapses in the lumbar spinal cords of mice with relapsing EAE, tissue expression of the pre-synaptic neuronal protein, synaptophysin, and the post-synaptic neuronal protein, MAP2, were assessed. By immunohistochemistry both proteins localized exclusively to spinal gray matter (Figure 2A), and by Western blot both proteins were dynamically regulated in directions opposite to paralysis severity (i.e., levels declined as paralysis scores increased, and vice versa) (Figure 2B). Focusing on the motor pathway at an ultrastructural level, the actual number of synapses found in direct contact with the perikarya of lumbar spinal motor neurons were notably reduced at peak disease but recovered as motor function returned back to normal (Figures 3A,B). At peak disease, few of these axosomatic synapses showed evidence that another cell had interposed a process between itself and the neuronal cell body; most appeared to have simply retracted from the cell perimeter (Figures 3C,D). Together, these data suggest that physical changes to the synapses projecting directly onto ventral motor neurons or their dendritic processes could contribute to the fluctuating paralysis that typifies relapsing-remitting EAE. They also show that dynamic modulation of these synaptic connections occurs in both temporal and spatial proximity to reactive astrocytes in surrounding gray matter.

Bottom Line: Taken together, these data support a model whereby proinflammatory cytokines inhibit SPARCL1 and/or augment SPARC expression by astrocytes in spinal gray matter that, in turn, cause either transient or sustained synaptic retraction from lumbar spinal motor neurons thereby regulating hind limb paralysis during EAE.Ongoing studies seek ways to alter this SPARCL1:SPARC expression ratio in favor of synapse reformation/maintenance and thus help to modulate neurologic deficits during times of inflammation.This could identify new astrocyte-targeted therapies for diseases such as multiple sclerosis.

View Article: PubMed Central - PubMed

Affiliation: Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan Medical School Ann Arbor, MI, USA.

ABSTRACT
The matricellular proteins, secreted protein acidic and rich in cysteine (SPARC) and SPARC-like 1 (SPARCL1), are produced by astrocytes and control excitatory synaptogenesis in the central nervous system. While SPARCL1 directly promotes excitatory synapse formation in vitro and in the developing nervous system in vivo, SPARC specifically antagonizes the synaptogenic actions of SPARCL1. We hypothesized these proteins also help maintain existing excitatory synapses in adult hosts, and that local inflammation in the spinal cord alters their production in a way that dynamically modulates motor synapses and impacts the severity of paralysis during experimental autoimmune encephalomyelitis (EAE) in mice. Using a spontaneously remitting EAE model, paralysis severity correlated inversely with both expression of synaptic proteins and the number of synapses in direct contact with the perikarya of motor neurons in spinal gray matter. In both remitting and non-remitting EAE models, paralysis severity also correlated inversely with sparcl1:sparc transcript and SPARCL1:SPARC protein ratios directly in lumbar spinal cord tissue. In vitro, astrocyte production of both SPARCL1 and SPARC was regulated by T cell-derived cytokines, causing dynamic modulation of the SPARCL1:SPARC expression ratio. Taken together, these data support a model whereby proinflammatory cytokines inhibit SPARCL1 and/or augment SPARC expression by astrocytes in spinal gray matter that, in turn, cause either transient or sustained synaptic retraction from lumbar spinal motor neurons thereby regulating hind limb paralysis during EAE. Ongoing studies seek ways to alter this SPARCL1:SPARC expression ratio in favor of synapse reformation/maintenance and thus help to modulate neurologic deficits during times of inflammation. This could identify new astrocyte-targeted therapies for diseases such as multiple sclerosis.

No MeSH data available.


Related in: MedlinePlus