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Oligodendrocytes (OLs) are specialized glial cells that myelinate CNS axons. OLs are generated throughout life from oligodendrocyte progenitor cells (OPCs) via a series of tightly controlled differentiation steps. Life-long myelination is essential for learning and to replace myelin lost in age-related pathologies such as Alzheimer's disease (AD) as well as white matter pathologies such as multiple sclerosis (MS). Notably, there is considerable myelin loss in the aging brain, which is accelerated in AD and underpins the failure of remyelination in secondary progressive MS. An important factor in age-related myelin loss is a marked decrease in the regenerative capacity of OPCs. In this review, we will contextualize recent advances in the key role of Epidermal Growth Factor (EGF) signaling in regulating multiple biological pathways in oligodendroglia that are dysregulated in aging. [ABSTRACT FROM AUTHOR]

Brain ageing is characterised by a decline in neuronal function and associated cognitive deficits. There is increasing evidence that myelin disruption is an important factor that contributes to the age‐related loss of brain plasticity and repair responses. In the brain, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Currently, a leading hypothesis points to ageing as a major reason for the ultimate breakdown of remyelination in Multiple Sclerosis (MS). However, an incomplete understanding of the cellular and molecular processes underlying brain ageing hinders the development of regenerative strategies. Here, our combined systems biology and neurobiological approach demonstrate that oligodendroglial and myelin genes are amongst the most altered in the ageing mouse cerebrum. This was underscored by the identification of causal links between signalling pathways and their downstream transcriptional networks that define oligodendroglial disruption in ageing. The results highlighted that the G‐protein coupled receptor Gpr17 is central to the disruption of OPCs in ageing and this was confirmed by genetic fate‐mapping and cellular analyses. Finally, we used systems biology strategies to identify therapeutic agents that rejuvenate OPCs and restore myelination in age‐related neuropathological contexts. [ABSTRACT FROM AUTHOR]

Models of central nervous system (CNS) function have historically been based on neurons and their synaptic contacts – the neuronal doctrine. This doctrine envisages glia as passive supportive cells. However, electrophysiological and imaging studies in brain slices show us that astrocytes, the most numerous cells in the brain, express a wide range of neurotransmitter receptors that are activated in response to synaptic activity. Furthermore, astrocytes communicate via calcium signals that are propagated over long distances by the release of ‘gliotransmitters’, the most abundant being adenosine triphosphate (ATP). This has led to the concept of the neuron–astroglial functional unit as the substrate of integration in the CNS. Recently, a novel glial cell type has been characterized by expression of the proteoglycan NG2. These NG2-glia receive presynaptic input from neurons and responds to neurotransmitters released at synapses. Now, studies on transgenic mice in which fluorescent proteins are specifically expressed by subclasses of glia are helping to address the question of where NG2-glia fit in the neuron–astroglial model of integrated brain function. NG2-glia, as well as astrocytes, have been shown to respond to neuronal and astroglial signals by raised intracellular calcium, which is a potential communications mechanism by which NG2-glia may be active partners in neuron–glial circuits. Moreover, a current concept of NG2-glia considers them to be ‘neural stem cells’ and an exciting prospect is that neuron–glial signalling may regulate the differentiation capacity of NG2-glia and their response to injury. [ABSTRACT FROM AUTHOR]

Abstract: Myelin formation by oligodendrocytes has been shown to be regulated by cyclic AMP (cAMP) signaling pathways and to depend on the resting membrane potential (RMP). We therefore examined whether cAMP regulates the RMP of myelin-forming oligodendrocytes in isolated intact optic nerves of rats. Oligodendrocytes exhibited a significant developmental shift in the RMP from −37 mV at postnatal day (P)6–8 to −67 mV at P21–30. The regulation of RMP was examined further in myelin-forming oligodendrocytes in nerves aged P15–20. Raising intracellular cAMP with dbcAMP or forskolin induced a significant hyperpolarization in myelin-forming oligodendrocytes by 10–15 mV. Inhibition of cAMP-dependent protein kinase (PKA) with KT5720 depolarized the oligodendroglial RMP −30 mV, which was only partly reversed by dbcAMP. In contrast, inhibition of cAMP specific phosphodiesterase with rolipram had no significant effect on the oligodendroglial RMP or the cAMP-mediated hyperpolarization. Blockade of Kir with 100 μm BaCl2 depolarized the oligodendrocyte RMP to −25 mV and inhibited the hyperpolarizing action of dbcAMP. The RMP was unaffected by agents that modulated ATP-sensitive potassium channels. The results provide evidence of a predominant role for Kir in setting the oligodendroglial RMP and show that cAMP regulates the oligodendroglial RMP, at least partly by a PKA-mediated pathway, possibly by modulating the activity of Kir. [Copyright &y& Elsevier]

Classic studies have recognized neurons and three glial elements in the central nervous system (CNS) – astrocytes, oligodendrocytes and microglia. The identification of novel glia that specifically express the NG2 chondroitin sulphate proteoglycan (CSPG) raises the possibility of a fifth element. Until recently, all NG2-expressing glia were considered to be oligodendrocyte precursor cells (OPCs) that persist in the adult CNS to generate oligodendrocytes throughout life. However, this narrow view of the function of ‘NG2-glia’ is being challenged. The majority of NG2-expressing glia in the adult CNS are a distinct class of cells that we have called ‘synantocytes’ (from the Greek synanto for contact). Synantocytes are stellate cells, with large process arborizations, and are exquisitely related to neurons. Individual cells traverse white and grey matter and form multiple contacts with neurons, astrocytes, oligodendrocytes and myelin. Synantocytes are an integral component of the ‘tetrapartite’ synapse, and provide a potential integrative neuron-glial communications pathway. Neuronal activity, glutamate and adenosine triphosphate (ATP) act on synantocyte receptors and evoke raised intracellular calcium. It remains to be seen whether this serves a physiological function, but synantocytes may be specialized to monitor signals from neurons and glia, and to respond to changes in the integrity of the CNS via their specific contacts and ion channel and receptor profiles. The general consequences of synantocyte activation are proliferation and phenotypic changes, resulting in glial scar formation, or regeneration of oligodendrocytes, and possibly neurons. [ABSTRACT FROM AUTHOR]

Abstract: The rodent optic nerve is a model tissue for the physiological investigation of axonal–glial interactions in a typical CNS white matter tract. There is strong evidence that nerve transmission is maintained by a considerable degree of dynamic signalling between axons and glia through a variety of mechanisms, such as regulation of the ionic environment, energy metabolism and calcium signalling. This review focuses on the methods used to examine axonal and glial functions and interactions, primarily in the rodent optic nerve. Techniques encompass intracellular microelectrodes, sucrose- and grease-gap recordings of membrane potentials, suction electrode to measure compound action potentials, the use of ion-sensitive electrodes, patch clamping and imaging. An overview of the advantages and drawbacks of each technique is given and the application of each to the understanding glial and axonal physiology is briefly discussed. [Copyright &y& Elsevier]

Abstract: Oligodendrocytes are the myelin-forming cells of the CNS and are lost in demyelinating diseases such as multiple sclerosis (MS). A role for fibroblast growth factor 2 (FGF2) has been proposed in the pathogenesis of demyelination and the failure of remyelination in experimental models of MS. However, the in vivo effects of FGF2 on oligodendrocytes and oligodendrocyte progenitors (OPCs) in the adult CNS had not previously been determined. To address this, FGF2 was delivered into the cerebrospinal fluid (CSF) of the IVth ventricle and its actions were examined on the anterior medullary velum (AMV), a thin tissue that partly roofs the IVth ventricle and is bathed by CSF. FGF2 was administered twice daily for 3 days and AMV were analysed using immunohistochemical labelling; saline was administered in controls. The results show that raised FGF2 induces severe disruption of mature oligodendrocytes and a marked loss of myelin. At the same time, FGF2 treatment resulted in the aberrant accumulation of immature oligodendrocytes with a premyelinating phenotype, together with NG2-expressing OPCs. Axons are patent within demyelinated lesions, and they are contacted but not ensheathed by surviving oligodendrocytes, newly formed premyelinating oligodendrocytes and OPCs. These results demonstrate that raised FGF2 induces demyelination in the adult CNS, and support a role for FGF2 in the pathogenesis of demyelination and regulation of remyelination in MS. [Copyright &y& Elsevier]

Abstract: We have previously shown that fibroblast growth factor 2 (FGF2) disrupts myelin formation by oligodendrocytes in vivo. Here, we have investigated the possibility that this is associated with changes in the expression of tau, a major microtubule-associated protein (MAP) involved in the production of myelin membranes by oligodendrocytes. FGF2, or saline vehicle in controls, was delivered into the brain ventricles of deeply anaesthetised young rats, and their actions were examined on the anterior medullary velum (AMV), a thin sheet of tissue that roofs part of the ventricular system underlying the cerebellum. The results show that the FGF2-induced loss of myelin is associated with increased immunostaining for tau within oligodendrocyte somata. Immunohistochemical and Western blot analyses demonstrate a 50% decrease in myelin-forming oligodendrocytes, axonal myelin sheaths, and levels of myelin-related proteins, with a correlative 100% increase in the level of tau. The results identify a potential mechanism by which FGF2-mediated accumulation of tau disrupts the transport of myelin-related gene products, resulting in disruption and eventual loss of oligodendrocytes and myelin, which are features of ischemia and a variety of demyelinating and neurodegenerative diseases. [Copyright &y& Elsevier]

Activation of purinoceptors by extracellular ATP is an important component of the glial response to injury in the central nervous system (CNS). ATP has been shown to evoke raised cytosolic [Ca2+] in astrocytes, oligodendrocytes, and microglia, the three major glial cell types in the CNS. Glial cells express a heterogenous collection of metabotropic P2Y and ionotropic P2X purinoceptors, which respectively mobilise Ca2+ from intracellular stores and trigger Ca2+ influx across the plasmalemma. It is likely that different receptors have distinct roles in glial cell physiology and pathology. Our studies on optic nerve glia in situ indicate that P2Y1 and P2Y2/4 receptors are activated at low ATP concentrations, suggesting they are the predominant purinoceptors mediating physiological Ca2+ signalling. Glia also express P2X1 and P2X3 purinoceptors, which mediate fast, rapidly desensitising current and may also be important in signalling. At high concentrations, such as occur in CNS injury, ATP induces large and prolonged increases in glial [Ca2+]i with a primary role for P2Y purinoceptors and inositol trisphosphate (IP3)-dependent release of Ca2+ from intracellular stores. In addition, we found that high concentrations of ATP activated a significant P2X component that did not desensitise or saturate and was dependent on extracellular Ca2+. These are characteristic properties of the P2X7 subtype, and we provide in situ evidence that application of the P2X7 receptor agonist benzoyl-benzoyl ATP (BzATP) evokes raised [Ca2+]i in optic nerve glia, and that the dye YO-PRO-1, which passes through pore-forming P2X7 receptors, is taken up by astrocytes, oligodendrocytes and microglia. Glia also express P2X2 and P2X4 receptors that are also pore-forming in the presence of sustained high ATP concentrations and which may also be important in the glial injury response. There is evidence that activation of P2 purinoceptors is a key step in triggering reactive changes in glial cells, including expression of immediate early genes, induction of extracellular signal regulated kinase and cyclooxygenase-2, synthesis of phospholipase A2, release of arachidonic acid, production of prostaglandins and release of interleukins. We show that the ATP-mediated increase in glial [Ca2+]i is potentiated by arachidonic acid and reduced by the inhibition of phospholipase A2 inhibition. Together, the results implicate ATP as a primary signalling molecule in glial cells and indicate specific roles for P2Y and P2X purinoceptors in glial cell pathology. [Copyright &y& Elsevier]