Glia
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It is a widespread notion that the proportion of glial to neuronal cells in the brain increases with brain size, to the point that glial cells represent "about 90% of all cells in the human brain." This notion, however, is wrong on both counts: neither does the glia/neuron ratio increase uniformly with brain size, nor do glial cells represent the majority of cells in the human brain. This review examines the origin of interest in the glia/neuron ratio; the original evidence that led to the notion that it increases with brain size; the extent to which this concept can be applied to white matter and whole brains and the recent supporting evidence that the glia/neuron ratio does not increase with brain size, but rather, and in surprisingly uniform fashion, with decreasing neuronal density due to increasing average neuronal cell size, across brain structures and species. Variations in the glia/neuron ratio are proposed to be related not to the supposed larger metabolic cost of larger neurons (given that this cost is not found to vary with neuronal density), but simply to the large variation in neuronal sizes across brain structures and species in the face of less overall variation in glial cell sizes, with interesting implications for brain physiology. The emerging evidence that the glia/neuron ratio varies uniformly across the different brain structures of mammalian species that diverged as early as 90 million years ago in evolution highlights how fundamental for brain function must be the interaction between glial cells and neurons.
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Plastic changes in white matter have received considerable attention in relation to normal cognitive function and learning. Oligodendrocytes and myelin, which constitute the white matter in the central nervous system, can respond to neuronal activity with prolonged depolarization of membrane potential and/or an increase in the intracellular Ca(2+) concentration. Depolarization of oligodendrocytes increases the conduction velocity of an action potential along axons myelinated by the depolarized oligodendrocytes, indicating that white matter shows functional plasticity, as well as structural plasticity. ⋯ Using whole-cell recordings from CA1 pyramidal cells and recordings of antidromic action potentials, we found that the early-onset short-lasting component included the synchronization of action potentials. Moreover, pharmacological analysis demonstrated that the activation of Ba(2+) -sensitive K(+) channels was involved in early- and late-onset facilitation, whereas 4-aminopyridine-sensitive K(+) channels were only involved in the early-onset component. These results demonstrate that oligodendrocyte depolarization induces short- and long-term functional plastic changes in the white matter of the hippocampus and plays active roles in brain functions.
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Excessive activation of glutamate receptors in spinal dorsal horn neurons is a key mechanism leading to abnormal neuronal activation in pathological pain conditions. Previous studies have shown that activation of glutamate receptors in the spinal dorsal horn is enhanced by impaired glial glutamate transporter functions and proinflammatory cytokines including interleukin-1 beta (IL-1β). In this study, we for the first time revealed that spinal glial glutamate transporter activities in the neuropathic animals are attenuated by endogenous IL-1β. ⋯ IL-1β reduces glial glutamate transporter activities through enhancing the endocytosis of both GLT-1 and GLAST glial glutamate transporters. The IL-1β induced trafficking of glial glutamate transporters is through the calcium/PKC signaling pathway, and the dynamin-dependent endocytosis, which is dependent on the integrity of actin filaments. The signaling pathway regulating glial glutamate transporters revealed in this study provides novel targets to attenuate aberrant activation of glutamate receptors in the spinal dorsal horn, which could ultimately help the development of analgesics.
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The immune-mediated central nervous system (CNS) demyelinating disorder multiple sclerosis (MS) is the most common neurological disease in young adults. One important goal of MS research is to identify strategies that will preserve oligodendrocytes (OLs) in MS lesions. During active myelination and remyelination, OLs synthesize large quantities of membrane proteins in the endoplasmic reticulum (ER), which may result in ER stress. ⋯ Unexpectedly, OL-PERK(ko/ko) mice develop normally and show no myelination defects. Nevertheless, EAE is exacerbated in these mice, which is correlated with increased OL loss, demyelination, and axonal degeneration. These data indicate that although not needed for developmental myelination, PERK signaling provides protection to OLs against inflammatory demyelination and suggest that the ISR in OLs could be a valuable target for future MS therapeutics.
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Satellite glial cells (SGCs) surrounding primary sensory neurons are similar to astrocytes of the central nervous system in that they buffer the extracellular environment via potassium and calcium channels and express the intermediate filament glial fibrillary acidic protein (GFAP). Peripheral nerve injury induces a reactive state in SGCs that includes SGC proliferation, increased SGC/SGC coupling via gap junctions, decreased inward rectifying potassium channel 4.1 (Kir 4.1) expression and increased expression of GFAP and the common neurotrophin receptor, p75NTR. In contrast, neuronal p75NTR expression, normally detected in ∼80% of adult rat sensory neurons, decreases in response to peripheral axotomy. ⋯ We found that reducing neuronal p75NTR protein expression in uninjured sensory neurons by intrathecal subarachnoid infusion of p75NTR-selective anti-sense oligodeoxynucleotides for one week was sufficient to induce a "reactive-like" state in the perineuronal SGCs akin to that normally observed following peripheral nerve injury. This reactive state included significantly increased SGC p75NTR, GFAP and gap junction protein connexin-43 protein expression, increased numbers of SGCs surrounding individual sensory neurons and decreased SGC Kir 4.1 channel expression. Collectively, this supports the tenet that reductions in target-derived trophic support leading to, or as a consequence of, reduced neuronal p75NTR expression plays a critical role in switching the SGC to a reactive state.