Hippocampal demyelination, a common feature of postmortem multiple
sclerosis (MS) brains, reduces neuronal gene expression and is a likely
contributor to the memory impairment that is found in greater than 40% of
individuals with (MS). How demyelination alters neuronal gene expression is
To explore if loss of hippocampal myelin alters expression of
neuronal microRNAs (miRNA), we compared miRNA profiles from myelinated and
demyelinated hippocampi from postmortem MS brains and performed validation
A network-based interaction analysis depicts a correlation between
increased neuronal miRNAs and decreased neuronal genes identified in our
previous study. The neuronal miRNA miR-124, was increased in demyelinated MS
hippocampi and targets mRNAs encoding 26 neuronal proteins that were
decreased in demyelinated hippocampus, including the ionotrophic glutamate
receptors, AMPA 2 and AMPA3. Hippocampal demyelination in mice also
increased miR-124, reduced expression of AMPA receptors and decreased memory
performance in water maze tests. Remyelination of the mouse hippocampus
reversed these changes.
We establish here that myelin alters neuronal gene expression and
function by modulating the levels of the neuronal miRNA miR-124. Inhibition
of miR-124 in hippocampal neurons may provide a therapeutic approach to
improve memory performance in MS patients.
Multiple sclerosis; myelin; microRNA
Generation and differentiation of new oligodendrocytes in demyelinated white matter is the best described repair process in the adult human brain. However, remyelinating capacity falters with age in patients with multiple sclerosis. (MS). Since demyelination of cerebral cortex is extensive in brains from MS patients, we investigated the capacity of cortical lesions to remyelinate and directly compared the extent of remyelination in lesions that involve cerebral cortex and adjacent subcortical white matter.
Postmortem brain tissue from 22 patients with MS (age 27 to 77 years) and 6 subjects without brain disease were analyzed. Regions of cerebral cortex with reduced myelin were examined for remyelination, oligodendrocyte progenitor cells, reactive astrocytes, and molecules that inhibit remyelination.
“New” oligodendrocytes that were actively forming myelin sheaths were identified in 30/42 remyelinated subpial cortical lesions, including lesions from three patients in their 70's. Oligodendrocyte progenitor cells were not decreased in demyelinated or remyelinated cortices when compared to adjacent normal-appearing cortex or controls. In demyelinated lesions involving cortex and adjacent white matter, the cortex showed greater remyelination, more actively remyelinating oligodendrocytes and fewer reactive astrocytes. Astrocytes in the white-matter, but not in cortical portions of these lesions, significantly up-regulate CD44, hyaluronan, and versican, molecules that form complexes that inhibit oligodendrocyte maturation and remyelination.
Endogenous remyelination of the cerebral cortex occurs in individuals with MS regardless of disease duration or chronological age of the patient. Cortical remyelination should be considered as a primary outcome measure in future clinical trials testing remyelination therapies.
multiple sclerosis; remyelination
Using the Illumina 450K array and a stringent statistical analysis with age and gender correction, we report genome-wide differences in DNA methylation between pathology-free regions derived from human multiple sclerosis–affected and control brains. Differences were subtle, but widespread and reproducible in an independent validation cohort. The transcriptional consequences of differential DNA methylation were further defined by genome-wide RNA-sequencing analysis and validated in two independent cohorts. Genes regulating oligodendrocyte survival, such as BCL2L2 and NDRG1, were hypermethylated and expressed at lower levels in multiple sclerosis–affected brains than in controls, while genes related to proteolytic processing (for example, LGMN, CTSZ) were hypomethylated and expressed at higher levels. These results were not due to differences in cellular composition between multiple sclerosis and controls. Thus, epigenomic changes in genes affecting oligodendrocyte susceptibility to damage are detected in pathology-free areas of multiple sclerosis–affected brains.
Capsaicin, an agonist of transient receptor potential vanilloid receptor 1, induces axonal degeneration of peripheral sensory nerves and is commonly used to treat painful sensory neuropathies. In this study, we investigated the role of mitochondrial dynamics in capsaicin-induced axonal degeneration. In capsaicin-treated rodent sensory axons, axonal swellings, decreased mitochondrial stationary site length and reduced mitochondrial transport preceded axonal degeneration. Increased axoplasmic Ca2+ mediated the alterations in mitochondrial length and transport. While sustaining mitochondrial transport did not reduce axonal swellings in capsaicin-treated axons, preventing mitochondrial fission by overexpression of mutant dynamin-related protein 1 increased mitochondrial length, retained mitochondrial membrane potentials and reduced axonal loss upon capsaicin treatment. These results establish that mitochondrial stationary site size significantly affects axonal integrity and suggest that inhibition of Ca2+-dependent mitochondrial fission facilitates mitochondrial function and axonal survival following activation of axonal cationic channels.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-014-1354-3) contains supplementary material, which is available to authorized users.
Mitochondria; Axonal swellings; Capsaicin; Miro; Drp1
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and the leading cause of non-traumatic neurological disability in young adults in the United States and Europe. The clinical disease course is variable and starts with reversible episodes of neurological disability in the third or fourth decade of life. Microarray-based comparative gene profiling provides a snapshot of genes underlying a particular condition. Several large scale microarray studies have been conducted using brain tissue from MS patients. In this review, we summarize existing data from different gene expression profiling studies and how they relate to understanding the pathogenesis of MS.
Multiple sclerosis; microarray; myelin
A remarkable pathological difference between grey matter lesions (GML) and white matter lesions (WML) in Multiple Sclerosis (MS) patients is the paucity of infiltrating leukocytes in GML. To better understand these pathological differences, we hypothesize that the chemokine monocyte chemotactic protein-1 (MCP-1 or CCL2), of importance for leukocyte migration, and its receptor CCR2 are more abundantly expressed in WML than in GML of MS patients. To this end, we analyzed CCL2 and CCR2 expression in the hippocampus, comprising WML and GML, of post-mortem MS patients, and of control subjects.
CCL2 and CCR2 mRNA were significantly increased in demyelinated MS hippocampus. Semi-quantification of CCL2 and CCR2 immunoreactivity showed that CCL2 is present in astrocytes only in active WML. CCR2 is upregulated in monocytes/macrophages or amoeboid microglia in active WML, and in ramified microglia in active GML, although to a lesser extent. As a follow-up, we observed a significantly increased CCL2 production by WM-, but not GM-derived astrocytes upon stimulation with bz-ATP in vitro. Finally, upon CCL2 stimulation, GM-derived microglia significantly increased their proliferation rate.
We conclude that within hippocampal lesions, CCL2 expression is mainly restricted to WML, whereas the receptor CCR2 is upregulated in both WML and GML. The relative absence of CCL2 in GML may explain the lack of infiltrating immune cells in this type of lesions. We propose that the divergent expression of CCL2 and CCR2 in WML and GML explains or contributes to the differences in WML and GML formation in MS.
Multiple sclerosis; Hippocampus; Monocyte chemotactic protein-1; Microglia; Astrocyte; Proliferation
Interleukin 17(IL-17) is a signature cytokine of Th17 cells. We previously reported that deletion of NF-κ B activator 1(Act1), the key transducer of IL-17R signaling, from the neuroectodermal lineage in mice (neurons, oligodendrocytes, astrocytes)results in attenuated severity of experimental autoimmune encephalomyelitis (EAE). Here we examined the cellular basis of this observation. EAE disease course was unaffected by deleting Act1 from neurons or mature oligodendrocytes and Act1 deletion from astrocytes only modestly affected disease course. Deletion of Act1 from NG2+ glia resulted in markedly reduced EAE severity. Furthermore, IL-17 induced characteristic inflammatory mediator expression in NG2+ glial cells. Additionally, IL-17 also exhibited strong inhibitory effects on the maturation of oligodendrocyte lineage cells in vitro and reduced their survival. These data identify NG2+ glia as the major CNS cellular target of IL-17 in EAE. The sensitivity of oligodendrocyte lineage cells to IL-17-mediated toxicity further suggests a direct link between inflammation and neurodegeneration in multiple sclerosis (MS).
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system. While the clinical impact of gray matter pathology in MS brains is unknown, 30–40% of MS patients demonstrate memory impairment. The molecular basis of this memory dysfunction has not yet been investigated in MS patients.
To investigate possible mechanisms of memory impairment in MS patients, we compared morphological and molecular changes in myelinated and demyelinated hippocampi from postmortem MS brains.
Demyelinated hippocampi had minimal neuronal loss but significant decreases in synaptic density. Neuronal proteins essential for axonal transport, synaptic plasticity, glutamate neurotransmission, glutamate homeostasis and memory/learning were significantly decreased in demyelinated hippocampi, but not in demyelinated motor cortices from MS brains.
Collectively, these data support hippocampal demyelination as a cause of synaptic alterations in MS patients and establish that the neuronal genes regulated by myelination reflect specific functions of neuronal subpopulations.
Multiple Sclerosis; hippocampus; demyelination; memory
Diffusion tensor imaging (DTI) measures in patients with multiple sclerosis (MS), particularly those measures associated with a specific white matter pathway, have consistently shown correlations with function. This study sought to investigate correlations between DTI measures in the fornix and common cognitive deficits in MS patients, including episodic memory, working memory and attention.
Materials and Methods
Patients with MS and group age- and sex-matched controls underwent high-resolution diffusion scanning (1-mm isotropic voxels) and cognitive testing. Manually drawn forniceal regions of interest were applied to individual maps of tensor-derived measures, and mean values of transverse diffusivity (TD), mean diffusivity (MD), longitudinal diffusivity (LD) and fractional anisotropy (FA) were calculated.
In 40 patients with MS [mean age±S.D.=42.55±9.1 years; Expanded Disability Status Scale (EDSS)=2.0±1.2; Multiple Sclerosis Functional Composite (MSFC) score=0.38±0.46] and 20 healthy controls (mean age±S.D.=41.35±9.7 years; EDSS=0.0±0; MSFC score=0.74±0.24), we found that FA, MD and TD values in the fornix were significantly different between groups (P<.03), and patient performance on the Brief Visuospatial Memory Test-Revised (BVMT-R) was correlated with DTI measures (P<.03).
These results are consistent with findings of axonal degeneration in MS and support the use of DTI as an indicator of disease progression.
Multiple sclerosis; Fornix; Diffusion tensor imaging; High spatial resolution; BVMT-R
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Due to its high prevalence, MS is the leading cause of non-traumatic neurological disability in young adults in the United States and Europe. The clinical disease course is variable and starts with reversible episodes of neurological disability in the third or fourth decade of life. This transforms into a disease of continuous and irreversible neurological decline by the sixth or seventh decade. Available therapies for MS patients have little benefit for patients who enter this irreversible phase of the disease. It is well established that irreversible loss of axons and neurons are the major cause of the irreversible and progressive neurological decline that most MS patients endure. This review discusses the etiology, mechanisms and progress made in determining the cause of axonal and neuronal loss in MS.
Multiple sclerosis; neurons; axons; myelin
Energy production presents a formidable challenge to axons as their mitochondria are synthesized and degraded in neuronal cell bodies. To meet the energy demands of nerve conduction, small mitochondria are transported to and enriched at mitochondrial stationary sites located throughout the axon. In this study, we investigated whether size and motility of mitochondria in small myelinated central nervous system axons was differentially regulated at nodes, and whether mitochondrial distribution and motility are modulated by axonal electrical activity. The size/volume of mitochondrial stationary sites was significantly larger in juxtaparanodal/internodal axoplasm than in nodal/paranodal axoplasm. By 3-dimensional electron microscopy, we observed that axonal mitochondrial stationary sites were composed of multiple mitochondria of varying length, except at nodes where mitochondria were uniformly short and frequently absent altogether. Mitochondrial transport speed was significantly reduced in nodal axoplasm when compared to internodal axoplasm. Increased axonal electrical activity decreased mitochondrial transport and increased the size of mitochondrial stationary sites in nodal/paranodal axoplasm. Decreased axonal electrical activity had the opposite effects. In cerebellar axons of the myelin deficient rat, which contains voltage-gated Na+ channel clusters but lacks paranodal specializations, axonal mitochondrial motility and stationary site size were similar at Na+ channel clusters and other axonal regions. These results demonstrate juxtaparanodal/internodal enrichment of stationary mitochondria and neuronal activity-dependent dynamic modulation of mitochondrial distribution and transport in nodal axoplasm. In addition, the modulation of mitochondrial distribution and motility requires oligodendrocyte-axon interactions at paranodal specializations.
myelination; mitochondria; axonal transport; node of Ranvier; action potential
Axonal degeneration contributes to permanent neurological disability in inherited and acquired diseases of myelin. Mitochondrial dysfunction has been proposed as a major contributor to this axonal degeneration. It remains to be determined, however, if myelination, demyelination or remyelination alter the size and distribution of axonal mitochondrial stationary sites or the rates of axonal mitochondrial transport. Using live myelinated rat dorsal root ganglion (DRG) cultures, we investigated whether myelination and lysolecithin-induced demyelination affect axonal mitochondria. Myelination increased the size of axonal stationary mitochondrial sites by 2.3 fold. Following demyelination, the size of axonal stationary mitochondrial sites was increased by an additional 2.2 fold and the transport velocity of motile mitochondria was increased by 47%. These measures returned to the levels of myelinated axons following remyelination. Demyelination induced activating transcription factor (ATF) 3 in DRG neurons. Knockdown of neuronal ATF3 by shRNA abolished the demyelination-induced increase in axonal mitochondrial transport and increased nitrotyrosine immunoreactivity in axonal mitochondria, suggesting that neuronal ATF3 expression and increased mitochondrial transport protect demyelinated axons from oxidative damage. In response to insufficient ATP production, demyelinated axons increase the size of stationary mitochondrial sites and thereby balance ATP production with the increased energy needs of nerve conduction.
Demyelination; mitochondria; adaptive response; axonal transport; axon; ATF3
We have identified a novel population of cells in the subventricular zone (SVZ) of the mammalian brain that expresses beta-4 tubulin (βT4) and has properties of primitive neuroectodermal cells. βT4 cells are scattered throughout the SVZ of the lateral ventricles in adult human brain, and are significantly increased in the SVZs bordering demyelinated white matter in multiple sclerosis brains. In human fetal brain, βT4 cell densities peak during the latter stages of gliogenesis, which occurs in the SVZ of the lateral ventricles. βT4 cells represent less than 2% of the cells present in neurospheres generated from postnatal rat brain, but >95% of cells in neurospheres treated with the anti-mitotic agent Ara-C. βT4 cells produce oligodendrocytes, neurons, and astrocytes in vitro. We compared the myelinating potential of βT4-positive cells with A2B5-positive oligodendrocyte progenitor cells following transplantation (25,000 cells) into postnatal day 3 (P3) myelin deficient rat brains. At P20, the progeny of βT4 cells myelinated up to 4 mm of the external capsule, which significantly exceeded that of transplanted A2B5-positive progenitor cells. Such extensive and rapid mature CNS cell generation by a relatively small number of transplanted cells provides in vivo support for the therapeutic potential of βT4 cells. We propose that βT4 cells are an endogenous cell source that can be recruited to promote neural repair in the adult telencephalon.
multiple sclerosis; subventricular zone; neural stem cell; myelin; oligodendrocyte; transplantation
Subcortical white matter in the adult human brain contains a population of interneurons that helps regulate cerebral blood flow. We investigated the fate of these neurons following subcortical white matter demyelination. Immunohistochemistry was used to examine neurons in normal-appearing subcortical white matter and seven acute and 59 chronic demyelinated lesions in brains from nine patients with multiple sclerosis and four controls. Seven acute and 44 of 59 chronic multiple sclerosis lesions had marked neuronal loss. Compared to surrounding normal-appearing white matter, the remaining 15 chronic multiple sclerosis lesions contained a 72% increase in mature interneuron density, increased synaptic densities and cells with phenotypic characteristics of immature neurons. Lesion areas with increased neuron densities contained a morphologically distinct population of activated microglia. Subventricular zones contiguous with demyelinated lesions also contained an increase in cells with phenotypes of neuronal precursors. These results support neurogenesis in a subpopulation of demyelinated subcortical white matter lesions in multiple sclerosis brains.
multiple sclerosis; white matter neurons; neurogenesis
The central nervous system (CNS) of terrestrial vertebrates underwent a prominent molecular change when a tetraspan membrane protein, myelin proteolipid protein (PLP), replaced the type I integral membrane protein, P0, as the major protein of myelin. To investigate possible reasons for this molecular switch, we genetically engineered mice to express P0 instead of PLP in CNS myelin. In the absence of PLP, the ancestral P0 provided a periodicity to mouse compact CNS myelin that was identical to mouse PNS myelin, where P0 is the major structural protein today. The PLP–P0 shift resulted in reduced myelin internode length, degeneration of myelinated axons, severe neurological disability, and a 50% reduction in lifespan. Mice with equal amounts of P0 and PLP in CNS myelin had a normal lifespan and no axonal degeneration. These data support the hypothesis that the P0–PLP shift during vertebrate evolution provided a vital neuroprotective function to myelin-forming CNS glia.
Mitochondrial content within axons increases following demyelination in the central nervous system, presumably as a response to the changes in energy needs of axons imposed by redistribution of sodium channels. Myelin sheaths can be restored in demyelinated axons and remyelination in some multiple sclerosis lesions is extensive, while in others it is incomplete or absent. The effects of remyelination on axonal mitochondrial content in multiple sclerosis, particularly whether remyelination completely reverses the mitochondrial changes that follow demyelination, are currently unknown. In this study, we analysed axonal mitochondria within demyelinated, remyelinated and myelinated axons in post-mortem tissue from patients with multiple sclerosis and controls, as well as in experimental models of demyelination and remyelination, in vivo and in vitro. Immunofluorescent labelling of mitochondria (porin, a voltage-dependent anion channel expressed on all mitochondria) and axons (neurofilament), and ultrastructural imaging showed that in both multiple sclerosis and experimental demyelination, mitochondrial content within remyelinated axons was significantly less than in acutely and chronically demyelinated axons but more numerous than in myelinated axons. The greater mitochondrial content within remyelinated, compared with myelinated, axons was due to an increase in density of porin elements whereas increase in size accounted for the change observed in demyelinated axons. The increase in mitochondrial content in remyelinated axons was associated with an increase in mitochondrial respiratory chain complex IV activity. In vitro studies showed a significant increase in the number of stationary mitochondria in remyelinated compared with myelinated and demyelinated axons. The number of mobile mitochondria in remyelinated axons did not significantly differ from myelinated axons, although significantly greater than in demyelinated axons. Our neuropathological data and findings in experimental demyelination and remyelination in vivo and in vitro are consistent with a partial amelioration of the supposed increase in energy demand of demyelinated axons by remyelination.
multiple sclerosis; axon; demyelination; mitochondria; remyelination
We show that normal peripheral nerve myelination depends on strict dosage of the most abundantly expressed myelin gene, myelin protein zero (Mpz). Transgenic mice containing extra copies of Mpz manifested a dose-dependent, dysmyelinating neuropathy, ranging from transient perinatal hypomyelination to arrested myelination and impaired sorting of axons by Schwann cells. Myelination was restored by breeding the transgene into the Mpz-null background, demonstrating that dysmyelination does not result from a structural alteration or Schwann cell-extrinsic effect of the transgenic P0 glycoprotein. Mpz mRNA overexpression ranged from 30–700%, whereas an increased level of P0 protein was detected only in nerves of low copy-number animals. Breeding experiments placed the threshold for dysmyelination between 30 and 80% Mpz overexpression. These data reveal new points in nerve development at which Schwann cells are susceptible to increased gene dosage, and suggest a novel basis for hereditary neuropathy.
axon sorting; myelin; neuropathy; Schwann cell; transgene
The bHLH transcription factor Olig1 promotes oligodendrocyte maturation and is required for myelin repair. In this report, we characterize an Olig1-regulated G-protein coupled receptor GPR17 whose function is to oppose the action of Olig1. GPR17 is restricted to oligodendrocyte lineage cells but downregulated during the peak period of myelination and in adulthood. Transgenic mice with sustained GPR17 expression in oligodendrocytes exhibit stereotypic features of myelinating disorders in the CNS. GPR17 overexpression inhibits oligodendrocyte differentiation and maturation both in vivo and in vitro. Conversely, GPR17 knockout mice display early onset of oligodendrocyte myelination. The opposing action of GPR17 on oligodendrocyte maturation reflects, at least partially, upregulation and nuclear translocation of the potent oligodendrocyte differentiation inhibitors ID2/4. Collectively, these findings suggest that GPR17 orchestrates the transition between immature and myelinating oligodendrocytes via an ID protein-mediated negative regulation, and may serve as a potential therapeutic target for CNS myelin repair.
oligodendrocyte differentiation and myelination; G-protein coupled receptor; Olig1; demyelinating diseases; ID proteins; multiple sclerosis
To compare leukocyte accumulation and expression of the chemokine receptor/ligand pair, CXCR4/CXCL12, in MRI-defined regions of interest (ROIs) from chronic multiple sclerosis (MS) brains. We studied the following ROIs: NAWM (normal appearing white matter); T2-only (regions abnormal only on T2-WI); T2/T1/MTR (regions abnormal on T2-weighted, T1-weighted images (-WI) and magnetization transfer ratio (MTR).
MRI-pathology correlations were performed on five secondary progressive MS (SPMS) cases. Based on imaging characteristics, thirty ROIs were excised. Using immunohistochemistry, we evaluated myelin status, leukocyte accumulation and CXCR4/CXCL12 expression in the MS ROIs and white matter regions from five non-neurological control cases.
Eight of ten T2/T1/MTR regions were chronic-active or chronic-inactive demyelinated lesions, whereas only two of ten T2-only regions were demyelinated and characterized as active or chronic active lesions. Equivalent numbers of CD68+ leukocytes (the predominant cell type) were present in myelinated T2-only regions as compared to NAWM. Parenchymal T-cells were significantly increased in T2/T1/MTR ROIs as compared to T2-only regions and NAWM. Expression of CXCR4 and phospho-CXCR4 was found on reactive microglia and macrophages in T2-only and T2/T1/MTR lesions. CXCL12 immunoreactivity was detected in astrocytes, astrocytic processes and vascular elements in inflamed MS lesions.
Inflammatory leukocyte accumulation was not increased in myelinated MS ROIs with abnormal T2 signal as compared with NAWM. Robust expression of CXCR4/CXCL12 on inflammatory elements in MS lesions highlights a role of this chemokine/receptor pair in CNS inflammation.
multiple sclerosis; MRI; inflammation; CXCR4; CXCL12; microglia
Axons in the peripheral (PNS) and central (CNS) nervous systems are ensheathed by multiple layers of tightly compacted myelin membranes. A series of cytoplasmic channels connect outer and inner margins of PNS, but not CNS myelin internodes. Membranes of these Schmidt-Lantermann (S-L) incisures contain the myelin-associated glycoprotein (MAG), but not P0 or proteolipid protein (PLP), the structural proteins of compact PNS (P0) and CNS (PLP) myelin. We show here that incisures are present in MAG-null and absent from P0-null PNS internodes. To test the possibility that P0 regulates incisure formation, we replaced PLP with P0 in CNS myelin. S-L incisures formed in P0-CNS myelin internodes. Furthermore, axoplasm ensheathed by 65% of the CNS incisures examined by electron microscopy had focal accumulations of organelles, indicating that these CNS incisures disrupt axonal transport. These data support the hypotheses that P0 protein is required for and can induce S-L incisures and that P0-induced CNS incisures can be detrimental to axonal function.
myelin; P0 protein; proteolipid protein; myelin-associated glycoprotein; axon; axonal transport
Previous studies have indicated that newly formed oligodendrocytes are dynamic cells whose production, survival, and differentiation depend upon axonal influences. This study has characterized the appearance and fate of newly formed oligodendrocytes in developing rat brain. Oligodendrocytes appear in predictable locations and radially extend DM-20–positive processes that cover 80-μm domains in the cortex and 40-μm domains in the corpus callosum. These premyelinating oligodendrocytes have one of two fates: they myelinate axons or degenerate. Between 7 and 21 d after birth, ∼20% of premyelinating oligodendrocytes identified in the cerebral cortex were degenerating. Oligodendrocytes that ensheathed axons expressed and selectively targeted proteolipid protein to compact myelin and did not degenerate. These observations support the hypothesis that axonal influences affect oligodendrocyte survival, differentiation, and expression of proteolipid protein gene products.
Microglia actively survey the brain microenvironment and play essential roles in sculpting synaptic connections during brain development. While microglial functions in the adult brain are less clear, activated microglia can closely appose neuronal cell bodies and displace axosomatic presynaptic terminals. Microglia-mediated stripping of presynaptic terminals is considered neuroprotective, but the cellular and molecular mechanisms are poorly defined. Using 3D electron microscopy, we demonstrate that activated microglia displace inhibitory presynaptic terminals from cortical neurons in adult mice. Electrophysiological recordings further establish that the reduction in inhibitory GABAergic synapses increased synchronized firing of cortical neurons in γ-frequency band. Increased neuronal activity results in the calcium-mediated activation of CaM kinase IV, phosphorylation of CREB, increased expression of antiapoptotic and neurotrophic molecules and reduced apoptosis of cortical neurons following injury. These results indicate that activated microglia can protect the adult brain by migrating to inhibitory synapses and displacing them from cortical neurons.
Microglia play essential roles in sculpting synaptic connections during brain development but their role in the adult brain is less clear. Here the authors show that activated microglia can prophylactically protect the adult rodent brain from injury by migrating to and displacing inhibitory synapses from cortical neurons.
Presently there is no clinically feasible imaging modality that can effectively detect cortical demyelination in patients with multiple sclerosis (MS). The objective of this study is to determine if clinically feasible magnetization transfer ratio (MTR) imaging is sensitive to cortical demyelination in MS.
MRI were acquired in situ on 7 recently deceased patients with MS using clinically feasible sequences at 3 T, including relatively high-resolution T1-weighted and proton density–weighted images with/without a magnetization transfer pulse for calculation of MTR. The brains were rapidly removed and placed in fixative. Multiple cortical regions from each brain were immunostained for myelin proteolipid protein and classified as mostly myelinated (MMctx), mostly demyelinated (MDctx), or intermediately demyelinated (IDctx). MRIs were registered with the cortical sections so that the cortex corresponding to each cortical section could be identified, along with adjacent subcortical white matter (WM). Mean cortical MTR normalized to mean WM MTR was calculated for each cortical region. Linear mixed-effects models were used to test if mean normalized cortical MTR was significantly lower in demyelinated cortex.
We found that mean normalized cortical MTR was significantly lower in cortical tissue with any demyelination (IDctx or MDctx) compared to MMctx (demyelinated cortex: least-squares mean [LSM] = 0.797, SE = 0.007; MMctx: LSM = 0.837, SE = 0.006; p = 0.01, n = 89).
This result demonstrates that clinically feasible MTR imaging is sensitive to cortical demyelination and suggests that MTR will be a useful tool to help detect MS cortical lesions in living patients with MS.