Metabotropic Glutamate Receptors Protect Oligodendrocytes from Acute Ischemia in the Mouse Optic Nerve.

Studies by Bruce Ransom and colleagues have made a major contribution to show that white matter is susceptible to ischemia/hypoxia. White matter contains axons and the glia that support them, notably myelinating oligodendrocytes, which are highly vulnerable to ischemic-hypoxic damage. Previous studies have shown that metabotropic GluRs (mGluRs) are cytoprotective for oligodendrocyte precursor cells and immature oligodendrocytes, but their potential role in adult white matter was unresolved. Here, we report that group 1 mGluR1/5 and group 2 mGluR3 subunits are expressed in optic nerves from mice aged postnatal day (P)8-12 and P30-35. We demonstrate that activation of group 1 mGluR protects oligodendrocytes against oxygen-glucose deprivation (OGD) in developing and young adult optic nerves. In contrast, group 2 mGluR are shown to be protective for oligodendrocytes against OGD in postnatal but not young adult optic nerves. The cytoprotective effect of group 1 mGluR requires activation of PKC, whilst group 2 mGluR are dependent on negatively regulating adenylyl cyclase and cAMP. Our results identify a role for mGluR in limiting injury of oligodendrocytes in developing and young adult white matter, which may be useful for protecting oligodendrocytes in neuropathologies involving excitoxicity and ischemia/hypoxia.

IL-1ß is induced in reactive astrocytes in the somatosensory cortex of rats with genetic absence epilepsy at the onset of spike-and-wave discharges, and contributes to their occurrence.

Interleukin (IL)-1ß plays a crucial role in the mechanisms of limbic seizures in rodent models of temporal lobe epilepsy. We addressed whether activation of the IL-1ß signaling occurs in rats with genetic absence epilepsy (GAERS) during the development of spike-and-wave discharges (SWDs). Moreover, we studied whether inhibition of IL-1ß biosynthesis in GAERS could affect SWD activity. IL-1ß expression and glia activation were studied by immunocytochemistry in the forebrain of GAERS at postnatal days (PN)14, PN20, and PN90 and in age-matched non-epileptic control Wistar rats. In PN14 GAERS, when no SWDs have developed yet, IL-1ß immunostaining was undetectable, and astrocytes and microglia showed a resting phenotype similar to control Wistar rats. In 3 out of 9 PN20 GAERS, IL-1ß was observed in activated astrocytes of the somatosensory cortex; the cytokine expression was associated with the occurrence of immature-type of SWDs. In all adult PN90 GAERS, when mature SWDs are established, IL-1ß was observed in reactive astrocytes of the somatosensory cortex but not in adjacent cortical areas or in extra-cortical regions. An age-dependent c-fos activation was found in the somatosensory cortex of GAERS with maximal levels reached in PN90 rats; c-fos was also induced in some thalamic nuclei in PN20 and PN90 GAERS. Inhibition of IL-1ß biosynthesis in PN90 GAERS by 4-day systemic administration of a specific ICE/Caspase-1 blocker, significantly reduced both SWD number and duration. These results show that IL-1ß is induced in reactive astrocytes of the somatosensory cortex of GAERS at the onset of SWDs. IL-1ß has pro-ictogenic properties in this model, and thus it may play a contributing role in the mechanisms underlying the occurrence of absence seizures.

Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer's disease.

There is increasing evidence that myelin disruption is related to cognitive decline in Alzheimer's disease (AD). In the CNS, myelin is produced by oligodendrocytes, which are generated throughout life by adult oligodendrocyte progenitor cells (OPCs), also known as NG2-glia. To address whether alterations in myelination are related to age-dependent changes in OPCs, we analyzed NG2 and myelin basic protein (MBP) immunolabelling in the hippocampus of 3×Tg-AD mice at 6 and 24 months of age, compared with non-Tg age-matched controls. There was an age-related decrease in MBP immunostaining and OPC density, together with a decline in the number of OPC sister cells, a measure of OPC replication. Notably, the loss of myelin and OPC sister cells occurred earlier at 6 months in 3xTg-AD, suggesting accelerated aging, although there was not a concomitant decline in OPC numbers at this age, suggesting the observed changes in myelin were not a consequence of replicative exhaustion, but possibly of OPC disruption or senescence. In line with this, a key finding is that compared to age-match controls, OPC displayed marked morphological atrophy at 6 months in 3xTg-AD followed by morphological hypertrophy at 24 months, as deduced from significant changes in total cell surface area, total cell volume, somata volume and branching of main processes. Moreover, we show that hypertrophic OPCs surround and infiltrate amyloid-ß (Aß) plaques, a key pathological hallmark of AD. The results indicate that OPCs undergo complex age-related remodeling in the hippocampus of the 3xTg-AD mouse model. We conclude that OPC disruption is an early pathological sign in AD and is a potential factor in accelerated myelin loss and cognitive decline.

A Central Role for ATP Signalling in Glial Interactions in the CNS.

The purine ATP has a prominent regulatory role in CNS function and pathology due to its actions on glial cells - microglia, astrocytes and oligodendrocytes. ATP serves as an apparently ubiquitous 'gliotransmitter' that is released by astrocytes and other cells to activate purine receptors on neighbouring cells. In pathology, the release of ATP mediates both tissue damage and repair by its direct effects on glial cell integrity and survival. The actions of ATP on glia are mediated via a wide range of receptors, broadly divided into ionotropic P2X and metabotropic (G-protein coupled receptors (GPCR)) P2Y receptors, of which there are multiple subtypes (P2X1-P2X7 and P2Y1-P2Y14). ATP-mediated interactions between astrocytes and microglia are at the centre of immune responses in the CNS, with prominent roles for the P2X4, P2X7, P2Y1, P2Y6 and P2Y12 receptor subtypes. In oligodendrocytes, P2X7 and P2Y1 receptor subtypes have a bipartite function in respectively mediating oligodendrocyte destruction and protection. Purine receptors mediate glial pathology, with prominent roles in ischemia, neuroinflammation, Multiple Scelerosis, neuropathic pain and traumatic injury. Notably, glial ATP signalling may be altered with ageing and is implicated in impaired myelination and immunity in Alzheimer's disease. Hence, glial purine receptors provide potential therapeutic targets in multiple neuropathologies, but the 'Jeckyll and Hyde' nature of purine signalling underscores the importance of further research and a comprehensive understanding of the roles of the different purine receptors in mediating tissue damage and repair.

mGluR5 protect astrocytes from ischemic damage in postnatal CNS white matter.

Astrocytes perform essential neuron-supporting functions in the central nervous system (CNS) and their disruption has devastating effects on neuronal integrity in multiple neuropathologies. Although astrocytes are considered resistant to most pathological insults, ischemia can result in astrocyte injury and astrocytes in postnatal white matter are particularly vulnerable. Metabotropic glutamate receptors (mGluR) are neuroprotective in ischemia and are widely expressed by astrocytes throughout CNS grey matter, but their potential cytoprotective role in astrocytes had not been determined. Here, we identify functional expression of group I mGluR in white matter astrocytes and demonstrate their activation protects astrocytes from ischemic damage in the postnatal mouse optic nerve. Optic nerve astrocytes are shown to express mGluR5 using immunolabelling of sections and explant cultures from transgenic reporter mice in which GFAP drives expression of EGFP. In addition, using Fluo-4 calcium imaging in isolated intact optic nerves, we show that the group I/II mGluR agonist ACPD and the specific group I mGluR agonist DHPG evoke glial Ca(2+) signals that were significantly inhibited by the group I mGluR antagonist AIDA. A key finding is that activation of group I mGluR protects astrocytes against oxygen-glucose deprivation (OGD) in situ, in isolated intact optic nerves from GFAP-EGFP mice. This study identifies a role for group I mGluR in protecting astrocytes against ischemia in postnatal white matter and suggests this may be a strategy for limiting damage in neuropathologies involving excitotoxity.