T-cell-mediated disruption of the neuronal microtubule network: correlation with early reversible axonal dysfunction in acute experimental autoimmune encephalomyelitis

During the course of the central nervous system autoimmune disease multiple sclerosis (MS), damage to myelin leads to neurological deficits attributable to demyelination and conduction failure. However, accumulating evidence has indicated that axonal injury is also a predictor of MS clinical disease. Using the animal model of MS, experimental autoimmune encephalomyelitis (EAE), we examined whether axonal dysfunction occurred early in disease and correlated with disease symptoms. We tracked axons during EAE by using transgenic mice that express yellow fluorescent protein (YFP) in neurons. At the onset of disease, we observed a loss of YFP fluorescence in the spinal cord in areas that coincided with immune cell infiltration, before prominent demyelination. These inflammatory lesions also exhibited evidence of axonal injury but not axonal loss. During the recovery phase of EAE, the return of YFP fluorescence occurred in parallel with the resolution of inflammation. Using in vitro cultured neurons expressing YFP, we demonstrated that encephalitogenic T cells alone directed the destabilization of microtubules within neurites, resulting in a change in the pattern of YFP fluorescence. This study provides evidence that encephalitogenic T cells directly cause reversible axonal dysfunction at the onset of neurological deficits during an acute central nervous system inflammatory attack.     

Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord

The epsilon 4 allele of the human apolipoprotein E gene (ApoE4) constitutes an important genetic risk factor for Alzheimer's disease. Recent experimental evidence suggests that human ApoE is expressed in neurons, in addition to being synthesized in glial cells. Moreover, brain regions in which neurons express ApoE seem to be most vulnerable to neurofibrillary pathology. The hypothesis that the expression pattern of human ApoE might be important for the pathogenesis of Alzheimer's disease was tested by generating transgenic mice that express human ApoE4 in neurons or in astrocytes of the central nervous system. Transgenic mice expressing human ApoE4 in neurons developed axonal degeneration and gliosis in brain and in spinal cord, resulting in reduced sensorimotor capacities. In these mice, axonal dilatations with accumulation of synaptophysin, neurofilaments, mitochondria, and vesicles were documented, suggesting impairment of axonal transport. In contrast, transgenic mice expressing human ApoE4 in astrocytes remained normal throughout life. These results suggest that expression of human ApoE in neurons of the central nervous system could contribute to impaired axonal transport and axonal degeneration. The possible contribution of hyperphosphorylation of protein Tau to the resulting phenotype is discussed.     

Withanoside IV improves hindlimb function by facilitating axonal growth and increase in peripheral nervous system myelin level after spinal cord injury

Although methylprednisolone is the clinically standard medication and almost the only therapy for spinal cord injury (SCI), its effect on functional recovery remains questionable. Transplantation strategies using sources such as neural stem cells and embryonic spinal cord still have some hurdles to overcome before practical applications become available. We therefore aimed to develop a practical medication for SCI. Per oral treatment with withanoside IV, which was previously shown to regenerate neuronal networks in the brain, improved locomotor functions in mice with SCI. In the spinal cord after SCI, axons were crushed in the white matter and gray matter, and central nervous system (CNS) myelin level decreased. In mice treated with withanoside IV (10micromol/kg body weight/day, for 21 days), axonal density and peripheral nervous system (PNS) myelin level increased. The loss of CNS myelin and increase in reactive gliosis were not affected by withanoside IV. These results suggest that oral administration of withanoside IV may ameliorate locomotor functions by facilitating both axonal regrowth and increase in PNS myelin level.     

Spinobulbar neurons in lamprey: cellular properties and synaptic interactions

An in vitro preparation of the nervous system of the lamprey, a lower vertebrate, was used to characterize the properties of spinal neurons with axons projecting to the brain stem [i.e., spinobulbar (SB) neurons)]. To identify SB neurons, extracellular electrodes on each side of the spinal cord near the obex recorded the axonal spikes of neurons impaled with sharp intracellular microelectrodes in the rostral spinal cord. The ascending spinal neurons (n = 144) included those with ipsilateral (iSB) (63/144), contralateral (cSB) (77/144), or bilateral (bSB) (4/144) axonal projections to the brain stem. Intracellular injection of biocytin revealed that the SB neurons had small- to medium-size somata and most had dendrites confined to the ipsilateral side of the cord, although about half of the cSB neurons also had contralateral dendrites. Most SB neurons had multiple axonal branches including descending axons. Electrophysiologically, the SB neurons were similar to other lamprey spinal neurons, firing spikes throughout long depolarizing pulses with some spike-frequency adaptation. Paired intracellular recordings between SB and reticulospinal (RS) neurons revealed that SB neurons made either excitatory or inhibitory synapses on RS neurons and the SB neurons received excitatory input from RS neurons. Mutual excitation and feedback inhibition between pairs of RS and SB neurons were observed. The SB neurons also received excitatory inputs from primary mechanosensory neurons (dorsal cells), and these same SB neurons were rhythmically active during fictive swimming, indicating that SB neurons convey both sensory and locomotor network information to the brain stem.     

Continued administration of ciliary neurotrophic factor protects mice from inflammatory pathology in experimental autoimmune encephalomyelitis

Multiple sclerosis is an inflammatory disease of the central nervous system that leads to loss of myelin and oligodendrocytes and damage to axons. We show that daily administration (days 8 to 24) of murine ciliary neurotrophic factor (CNTF), a neurotrophic factor that has been described as a survival and differentiation factor for neurons and oligodendrocytes, significantly ameliorates the clinical course of a mouse model of multiple sclerosis. In the acute phase of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein peptide 35-55, treatment with CNTF did not change the peripheral immune response but did reduce the number of perivascular infiltrates and T cells and the level of diffuse microglial activation in spinal cord. Blood brain barrier permeability was significantly reduced in CNTF-treated animals. Beneficial effects of CNTF did not persist after it was withdrawn. After cessation of CNTF treatment, inflammation and symptoms returned to control levels. However, slight but significantly higher numbers of oligodendrocytes, NG2-positive cells, axons, and neurons were observed in mice that had been treated with high concentrations of CNTF. Our results show that CNTF inhibits inflammation in the spinal cord, resulting in amelioration of the clinical course of experimental autoimmune encephalomyelitis during time of treatment.     

Ganglioside-induced regeneration and reestablishment of axonal continuity in spinal cord-transected rats

In this study we examined the effect of chronic GM-1 ganglioside treatment on the reestablishment of axonal continuity and functional recovery in spinal cord-transected rats. Previous studies have shown that chronic treatment with GM-1 ganglioside is effective in producing regeneration of lesioned mesostriatal dopaminergic neurons in the central nervous system [1, 2]. In addition, GM-1 ganglioside advances peripheral nerve regeneration following nerve crush injury [12]. Axonal continuity was determined by the ability of the spinal cord to transport horseradish peroxidase across the region of transection. Comparisons between ganglioside-treated and saline-treated controls showed that ganglioside treatment resulted in the reestablishment of axonal continuity between the spinal cord distal to the level of the transection and the brainstem. Saline-treated controls showed little evidence of axonal continuity between these two regions. Thus gangliosides induce reestablishment of axonal continuity and thereby could advance functional recovery in rats following spinal cord transection.     

Evidence for loss of myelinated input to the spinal cord in senescent rats.

Impaired sensory perception is a well-established stigma of aging and whereas loss of dorsal root ganglion (DRG) neurons is marginal there is a specific pattern of reduced peripheral sensory innervation. To resolve if similar regressive processes occur in the central innervation, peripheral nerves were injected with markers for unmyelinated (isolectin B4) or myelinated (cholera toxin B subunit; CTB) DRG neurons. The results were a dramatic decrease of primary sensory endings in the spinal cord of aged rats following transganglionic labeling with CTB, and also to a lesser degree with B4. Profile counting and frequency estimates showed that the reduction of CTB labeled profiles not was caused by impaired axonal uptake, slowed axonal transport of CTB, or by a loss of myelinated fibers in the peripheral nerve. At the ultrastructural level, peripheral nerves showed the classical hallmarks of aging, with more pronounced alterations in myelinated than unmyelinated axons. Taken together, sensory deprivation in senescence appears to be a distal process in DRG neurons involving both peripheral and central target disconnection. Finally, preliminary data indicates that the substantial reduction in mechanoreceptive input to the central nervous system co-varies with the degree of sensorimotor impairment of the aged individuals.     

大鼠胚胎脑和脊髓神经干细胞分化特性比较

体外分离大鼠胚胎脑和脊髓神经干细胞,经培养传代后,撤除生长因子(bFGF和EGF)并给予 1%胎牛血清促其自然分化,然后比较两者的分化规律,以及传代次数对分化的影响。结果发现:在完全相同的培养条件下,来源于脑和脊髓的神经干细胞均可分化为神经元、少突胶质细胞和星形胶质细胞,但两者分化为神经元的能力均随细胞体外传代次数的增加而显著下降 (P<0. 05);此外,脑来源的神经干细胞分化为神经元的能力远高于脊髓来源的神经干细胞 (P<0. 01)。提示,来自中枢神经系统不同部位的神经干细胞在分化潜力上存在差别,体外传代会影响神经干细胞的分化能力。     

Localization of Reversion-Induced LIM Protein (RIL) in the Rat Central Nervous System

Reversion-induced LIM protein (RIL) is a member of the ALP (actinin-associated LIM protein) subfamily of the PDZ/LIM protein family. RIL serves as an adaptor protein and seems to regulate cytoskeletons. Immunoblotting suggested that RIL is concentrated in the astrocytes in the central nervous system. We then examined the expression and localization of RIL in the rat central nervous system and compared it with that of water channel aquaporin 4 (AQP4). RIL was concentrated in the cells of ependyma lining the ventricles in the brain and the central canal in the spinal cord. In most parts of the central nervous system, RIL was expressed in the astrocytes that expressed AQP4. Double-labeling studies showed that RIL was concentrated in the cytoplasm of astrocytes where glial fibrillary acidic protein was enriched as well as in the AQP4-enriched regions such as the endfeet or glia limitans. RIL was also present in some neurons such as Purkinje cells in the cerebellum and some neurons in the brain stem. Differential expression of RIL suggests that it may be involved in the regulation of the central nervous system.     

Nogo and Nogo-66 receptor in human and chick: implications for development and regeneration.

Antibodies to the myelin protein Nogo increase axonal regrowth after central nervous system injury. We have investigated whether Nogo expression contributes to loss of regenerative potential during development by using chick embryos, which regenerate their spinal cord until embryonic day (E) 13, when myelination begins. We show that Nogo-A and the Nogo receptor (NgR) are developmentally regulated both in chick and human embryos, are first detected at developmental stages when the chick spinal cord regenerates, and are not down-regulated after injury at permissive stages for regeneration. Therefore, expression of Nogo-A and NgR in pre-E13 chick spinal cords is not sufficient to inhibit regeneration. Nogo-A expression in the chick early embryo is primarily observed in axons, whereas NgR is mainly located on neuronal cell bodies, both in spinal cord and eye, and in striated muscle including the heart. With the onset of myelination, there is down-regulation of Nogo-A expression in neurons. Therefore, loss of regenerative potential might be linked to changes in its cellular localization. The possibility that only Nogo expressed in mature oligodendrocytes can exercise inhibitory effects would reconcile the lack of inhibition we observe in developing chick spinal cords before the onset of myelination with evidence from other laboratories on the inhibitory effects of Nogo in mature central nervous system. The distinctive and complementary patterns of Nogo-A and NgR expression and their conservation throughout evolution support the view that Nogo signaling represents a key pathway in nervous system and striated muscle development. Its putative role in target innervation and establishment of neural circuitry is discussed.     

Cellular and regional expression of glutamate dehydrogenase in the rat nervous system: non-radioactive in situ hybridization and comparative immunocytochemistry.

In the central nervous system glutamate dehydrogenase appears to be strongly involved in the metabolism of transmitter glutamate and plays a role in the pathogenesis of neurodegenerative disorders. In order to identify unequivocally the neural cell types expressing this enzyme, non-radioactive in situ hybridization, using a complementary RNA probe and oligonucleotide probes, was applied to sections of the rat central nervous system and, for comparison with peripheral neural cells, to cervical spinal ganglia. The results were complemented by immunocytochemical studies using a polyclonal antibody against purified glutamate dehydrodenase. Glutamate dehydrogenase messenger RNA was detectable at varying amounts in neurons and glial cells (i.e. astrocytes, oligodendrocytes, Bergmann glia, ependymal cells, epithelial cells of the plexus choroideus) throughout the central nervous system and in neurons and satellite cells of spinal ganglia. In some neuronal populations (e.g., pyramidal cells of the hippocampus, motoneurons of the spinal cord and spinal ganglia neurons) messenger RNA-labelling was higher than in other central nervous system neurons. This is remarkable because the immunostaining of neurons in the central nervous system regions studied was at best weak, whereas a predominantly high level of immunoreactivity was detected in astrocytes (and Bergmann glia). Thus, in neurons of the central nervous system, the detected levels of glutamate dehydrogenase messenger RNA and protein seem to be at variance whereas in peripheral neurons of spinal ganglia both in situ hybridization labelling and immunostaining are intense.     

The neuronal response to injury as visualized by immunostaining of class III beta-tubulin in the rat

The neuronal response to trauma of the brain and spinal cord was examined by staining sections of injured central nervous system (CNS) with a monoclonal antibody (TuJ1) that recognizes class III beta-tubulin exclusively. Because class III beta-tubulin is expressed by neurons and not by glia, this monoclonal antibody stains neuronal cell bodies, dendrites, axons and axonal terminations darkly with a pale staining background. Thus, the TuJ1 antibody is extremely useful, revealing the fine details of axons and their terminations, as well as significant injury-related alterations in the composition of the somatic cytoskeleton.     

Robust CNS regeneration after complete spinal cord transection using aligned poly-L-lactic acid microfibers

Following spinal cord injury, axons fail to regenerate without exogenous intervention. In this study we report that aligned microfiber-based grafts foster robust regeneration of vascularized CNS tissue. Film, random, and aligned microfiber-based conduits were grafted into a 3 mm thoracic rat spinal cord gap created by complete transection. Over the course of 4 weeks, microtopography presented by aligned or random poly-L-lactic acid microfibers facilitated infiltration of host tissue, and the initial 3 mm gap was closed by endogenous cell populations. This bulk tissue response was composed of regenerating axons accompanied by morphologically aligned astrocytes. Aligned fibers promoted long distance (2055 ± 150 μm), rostrocaudal axonal regeneration, significantly greater than random fiber (1162 ± 87 μm) and film (413 ± 199 μm) controls. Retrograde tracing indicated that regenerating axons originated from propriospinal neurons of the rostral spinal cord, and supraspinal neurons of the reticular formation, red nucleus, raphe and vestibular nuclei. Our findings outline a form of regeneration within the central nervous system that holds important implications for regeneration biology.     

Electric field-guided neuron migration: a novel approach in neurogenesis

Effective directional neuron migration is crucial in development of the central nervous system and for neurogenesis. Endogenous electrical signals are present in many developing systems and crucial cellular behaviors such as neuronal cell division, cell migration, and cell differentiation are all under the influence of such endogenous electrical cues. Preclinical in vivo studies have used electric fields (EFs) to attempt to enhance regrowth of damaged spinal cord axons with some success. Recent evidence shows that small EFs not only guide axonal growth, but also direct the earlier events of neuronal migration and neuronal cell division. This raises the possibility that applied or endogenous EFs, perhaps in combination, may direct transplanted neural stem cells, or regenerating neurons, to the desired site after brain injury or neuron degeneration. The high complexity of both structure and function of the nervous system, however, poses significant challenges to techniques for applying EFs to promote neurogenesis. The evolution of functional biomaterials and nanotechnology may provide promising solutions for the application of EFs in guiding neuron migration and neurogenesis within the central nervous system.     

Single-cell analysis of mtDNA in amyotrophic lateral sclerosis: towards the characterization of individual neurons in neurodegenerative disorders

Laser microdissection offers the separate analysis of neuronal cells within the central nervous system in certain neurodegenerative diseases. We have established the amplification of a common deletion of mitochondrial DNA (mtDNA) on the basis of single microdissected neurons. Using brain and spinal cord tissue from patients suffering from amyotrophic lateral sclerosis (ALS) and healthy controls, we detected the 5 kB common deletion of mtDNA in motor neurons from ALS and control cases. The deletion was also present in non-motor regions from diseased patients and controls, suggesting that the presence of the mtDNA deletion is not associated with the neuronal death in specific areas of the central nervous system in ALS.     

Peripheral and central nervous system lesions caused by triethyl- and trimethyltin salts in rats

Both trimethyltin and triethyltin salts are known to produce toxic lesions in the central nervous system. Triethyltin intoxication has been associated with central intramyelin edema, while trimethyltin has been shown to produce neuronal necrosis in selected limbic and sensory regions of the brain. Only scant attention has been paid to peripheral nerves of animals treated with alkyltins. In this study, we have treated rats with 6 or 8 mg/kg trimethyltin, and 1, 2, 4, 6, or 8 mg/kg triethyltin (single or multiple exposure), and evaluated in detail at the light microscope level both central and peripheral nervous system lesions. In addition to the central neuron necrosis or myelin edema described previously, both compounds produced peripheral axon degeneration and chromatolysis of large spinal cord and brain stem neurons. Chromatolysis was seen in reticular neurons of the brain stem and ventral horn or spinal cord in rats receiving high doses (6 or 8 mg/kg) of triethyltin, and in these same areas plus mesencephalic trigeminal nucleus in animals treated with trimethyltin. Wallerian-like degeneration of peripheral axons was seen in sciatic and tibial nerve and ventral roots of animals receiving 3 injections of 4 mg/kg or single or multiple injections of 6 or 8 mg/kg triethyltin. Axon degeneration was also seen in sciatic and tibial nerves 21 days after a single exposure to 8 mg/kg trimethyltin. Since myelin edema is believed to be reversible, the axonal changes described here may be of greater clinical significance in relation to human exposure.     

Distribution of NADPH diaphorase-containing neurons in the pigeon central nervous system

The aim of the present study was to determine the distribution of nitric oxide-synthesizing neurons in the pigeon brain and spinal cord. Tissue sections were stained for reduced nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d). In the telencephalon, intensely stained neurons with dendrites extending distally were seen in most regions. The ectostriatum was characterized by intensely and diffusely stained neuropil. In the diencephalon, intensely positive neurons were seen in the lateral hypothalamic region and lateral mammillary nucleus. In the mesencephalon, intensely stained, multipolar neurons were abundantly scattered in the central gray, nucleus intercollicularis, reticular formation, nucleus tegmenti pedunculo-pontinus, pars compacta, area ventralis of Tsai, and ansa lenticularis. In the rhombencephalon, positively-stained neurons were found in the pontine nuclei and reticular formation. The cerebellar cortex, except for Purkinje cells, was a preferential region for NADPH-d activity. Positive end-bulbs made contact on somata in the nucleus magnocellularis cochlearis. In the spinal cord, NADPH-d positive neurons were seen in layer II and the marginal nucleus. Our results demonstrated that the distribution of NADPH-d-containing neurons in the pigeon brain and spinal cord is more complex than in other avian species. Our findings indicate that NADPH-d-containing neurons are present in several sensory pathways, including olfactory, visual, auditory, and somatosensory tracts, although some nuclei in each system did not show NADPH-d activity. The wide distribution of NADPH-d activity in the pigeon CNS suggests that nitric oxide modulates sensory transmission in avian central nervous system.     

Electrophysiological characterization of putative C1 adrenergic neurons in the rat

Recent studies in the rat have demonstrated that at least two populations of sympathoexcitatory reticulospinal neurons reside in the nucleus reticularis rostroventrolateralis. It appears that only one of these populations consists of C1 adrenergic neurons. The present study used both double-labeling (one retrograde tracer and immunohistochemistry) and triple-labeling (two retrograde tracers and immunohistochemistry) to determine if C1 adrenergic neurons, which are immunoreactive for phenylethanolamine N-methyltransferase, exhibit a projection pattern that is sufficiently unique to permit the electrophysiological discrimination between C1 adrenergic and non-adrenergic neurons in the nucleus reticularis rostroventrolateralis. Double-labeling experiments indicated that 71% (range: 53-80) of phenylethanolamine-N-methyltransferase-immunoreactive neurons in the nucleus reticularis rostroventrolateralis could be retrogradely labeled from the thoracic cord, as were 76% (range: 67-94) following tracer injection in the central tegmental tract at pontine levels. Triple-labeling experiments indicated that 88% (range: 82-93) of nucleus reticularis rostroventrolateralis neurons with projections to both spinal cord and central tegmental tract were phenylethanolamine-N-methyltransferase-immunoreactive. Single-unit recording, in nucleus reticularis rostroventrolateralis, was used to identify antidromic potentials elicted from stimulation sites in the spinal cord and/or central tegmental tract. Since clonidine is known to reduce central adrenaline turnover, sensitivity to this drug was used to identify putative adrenergic neurons. Twenty-six nucleus reticularis rostroventrolateralis neurons with axonal projections to both the ipsilateral spinal cord and the central tegmental tract were recorded in halothane-anesthetized rats. All these cells were barosensitive, pulse-modulated, and 16 of the 16 cells tested exhibited a 66 +/- 8% reduction in activity upon the intravenous administration of clonidine (20 micrograms/kg). Most (13 out of 16) exhibited a strong respiratory modulation. The conduction velocity of their spinal collateral was generally low (0.9 +/- 0.1 m/s) and their firing rate moderate (7.4 +/- 1.2 spikes/s). Forty-three nucleus reticularis rostroventrolateralis cells with axonal projections exclusively to the thoracic cord were studied for comparison. These cells were strongly barosensitive and pulse-synchronous, had a high discharge rate (25 +/- 3 spikes/s) and a moderate conduction velocity (3.4 +/- 0.3 m/s). Only one of the 15 cells tested was inhibited by clonidine and only two to these 15 cells exhibited a detectable respiratory modulation. Thus barosensitive nucleus reticularis rostroventrolateralis neurons with axonal projections to both the spinal cord and the central tegmental tract likely belong to the C1 adrenergic cell group. It is concluded that this subgroup of adrenergic neurons probably subserves a vasomotor function.     

Demyelination and axonal dystrophy in alpha A-crystallin transgenic mice

Homozygous mice transgenic for alphaA-crystallin, one of the structural eye lens proteins, developed hindlimb paralysis after 8 weeks of age. To unravel the pathogenesis of this unexpected finding and the possible role of alphaA-crystallin in this pathological process, mice were subjected to a histopathological and immunohistochemical investigation. Immunohistochemistry showed large deposits of alphaA-crystallin in the astrocytes of the spinal cord, and in the Schwann cells of dorsal roots and sciatic nerves. Additionally, microscopy showed dystrophic axons in the spinal cord and digestion chambers as a sign of ongoing demyelination in dorsal roots and sciatic nerves. Apart from a few areas with slight alphaA-crystallin-immunopositive structures, the brain was normal. Because the alphaA-crystallin protein expression appeared in specific cells of the nervous system (astrocytes and Schwann cells), the most plausible explanation for the paralysis is a disturbance of cell function caused by the excessive intracytoplasmic accumulation of the alphaA-crystallin protein. This is followed by a sequence of secondary changes (demyelination, axonal dystrophy) and finally arthrosis. In conclusion, alphaA-crystallin transgenic mice develop a peripheral and central neuropathy primarily affecting spinal cord areas at the dorsal side, dorsal root and sciatic nerve.     

Downregulation of microglial keratan sulfate proteoglycans coincident with lymphomonocytic infiltration of the rat central nervous system.

The monoclonal antibody (MAb) 5D4 against a keratan sulfate (KS) epitope of bovine cartilage proteoglycan stains ramified microglia in the rat brain. In this study we show that 5D4-positive microglia is abundant in the normal rat spinal cord and nearly absent during both the active and recovery phase of experimental autoimmune encephalomyelitis (EAE) in myelin-immunized Lewis rats. In contrast, during Wallerian degeneration of the optic nerve the density of KS-immunoreactive microglia remains constant. KS immunoreactivity is absent from both normal and transected sciatic nerves, and spinal nerve roots. On immunoblots of spinal cord extracts MAb 5D4 stains a novel type of KS proteoglycans (KSPGs) with an apparent molecular weight mainly between 140 and 200 kd, which significantly decrease in acute EAE. Our data suggest that high levels of KSPG expression correlate to a downregulated immunophenotype of resident macrophages in the nervous system. The lack of detectable KS in peripheral nerve points to a divergent differentiation of bone marrow-derived resident macrophages in the peripheral and central nervous systems and may partially account for the rapid macrophage response to axonal injury in the peripheral nervous system. Downregulation of microglial KSPG could be a prerequisite for a rapid inflammatory response in the central nervous system.