Abstract Oligodendrocytes are crucial to the function of the mammalian brain: they increase the action potential conduction speed for a given axon diameter and thus facilitate the rapid flow of ...information between different brain areas. The proliferation and differentiation of developing oligodendrocytes, and their myelination of axons, are partly controlled by neurotransmitters. In addition, in models of conditions like stroke, periventricular leukomalacia leading to cerebral palsy, spinal cord injury and multiple sclerosis, oligodendrocytes are damaged by glutamate and, contrary to dogma, it has recently been discovered that this damage is mediated in part by N -methyl- d -aspartate receptors. Mutations in oligodendrocyte neurotransmitter receptors or their interacting proteins may cause defects in CNS function. Here we review the roles of neurotransmitter receptors in the normal function, and malfunction in pathological conditions, of oligodendrocytes.
Cerebellar granule cells are inhibited phasically by GABA released synaptically from Golgi cells, but are inhibited more powerfully
by tonic activity of high affinity α 6 subunit-containing GABA A ...receptors. During development the tonic activity is generated by the accumulation of GABA released by action potentials,
but in the adult the tonic activity is independent of action potentials. Here we show that in adult rats the tonic activation
of GABA A receptors is produced by non-vesicular transmitter release and is reduced by the activity of GAT-1 and GAT-3 GABA transporters,
demonstrating that alterations of GABA uptake will modulate information flow through granule cells. Acetylcholine (ACh) evokes
a large Ca 2+ -dependent but action potential-independent release of GABA, which activates α 6 subunit-containing GABA A receptors. These data show that three separate modes of transmitter release can activate GABA A receptors in adult cerebellar granule cells: action potential-evoked exocytotic GABA release, non-vesicular release, and
ACh-evoked Ca 2+ -dependent release independent of action potentials. The relative magnitudes of the inhibitory charge transfers generated
by action potential-evoked release (during high frequency stimulation of the mossy fibres), tonic inhibition and superfused
ACh are 1:3:12, indicating that tonic and ACh-mediated inhibition may play a major role in regulating granule cell firing.
Abstract The relative distribution of the excitatory amino acid transporter 2 (EAAT2) between synaptic terminals and astroglia, and the importance of EAAT2 for the uptake into terminals is still ...unresolved. Here we have used antibodies to glutaraldehyde-fixed d -aspartate to identify electron microscopically the sites of d -aspartate accumulation in hippocampal slices. About 3/4 of all terminals in the stratum radiatum CA1 accumulated d -aspartate-immunoreactivity by an active dihydrokainate-sensitive mechanism which was absent in EAAT2 glutamate transporter knockout mice. These terminals were responsible for more than half of all d -aspartate uptake of external substrate in the slices. This is unexpected as EAAT2-immunoreactivity observed in intact brain tissue is mainly associated with astroglia. However, when examining synaptosomes and slice preparations where the extracellular space is larger than in perfusion fixed tissue, it was confirmed that most EAAT2 is in astroglia (about 80%). Neither d -aspartate uptake nor EAAT2 protein was detected in dendritic spines. About 6% of the EAAT2-immunoreactivity was detected in the plasma membrane of synaptic terminals (both within and outside of the synaptic cleft). Most of the remaining immunoreactivity (8%) was found in axons where it was distributed in a plasma membrane surface area several times larger than that of astroglia. This explains why the densities of neuronal EAAT2 are low despite high levels of mRNA in CA3 pyramidal cell bodies, but not why EAAT2 in terminals account for more than half of the uptake of exogenous substrate by hippocampal slice preparations. This and the relative amount of terminal versus glial uptake in the intact brain remain to be discovered.
Abstract Glutamatergic signaling has been exceptionally well characterized in the brain's gray matter, where it underlies fast information processing, learning and memory, and also generates the ...neuronal damage that occurs in pathological conditions such as stroke. The role of glutamatergic signaling in the white matter, an area until recently thought to be devoid of synapses, is less well understood. Here we review what is known, and highlight what is not known, of glutamatergic signaling in the white matter. We focus on how glutamate is released, the location and properties of the receptors it acts on, the interacting molecules that may regulate trafficking or signaling of the receptors, the possible functional roles of glutamate in the white matter, and its pathological effects including the possibility of treating white matter disorders with glutamate receptor blockers.
The retina provides an example of effects, the visually perceived 'phosphenes', being generated in nervous tissue by external electric or magnetic fields of low frequency and intensity. What is known ...about the cellular mechanisms by which the phosphenes are generated is reviewed, whether they provide useful information for setting limits on the magnitude of induced electric fields to which nervous tissue can be safely exposed is assessed, and some difficulties in translating these values of internal fields into safe values of external electric or magnetic fields are considered.
Elevations of the levels of N-acetyl-aspartyl-glutamate (NAAG) and N-acetyl-aspartate (NAA) are associated with myelin loss in the leucodystrophies Canavan's disease and Pelizaeus-Merzbacher-like ...disease. NAAG and NAA can activate and antagonize neuronal N-methyl-D-aspartate (NMDA) receptors, and also act on group II metabotropic glutamate receptors. Oligodendrocytes and their precursors have recently been shown to express NMDA receptors, and activation of these receptors in ischaemia leads to the death of oligodendrocyte precursors and the loss of myelin. This raises the possibility that the failure to develop myelin, or demyelination, occurring in the leucodystrophies could reflect an action of NAAG or NAA on oligodendrocyte NMDA receptors. However, since the putative subunit composition of NMDA receptors on oligodendrocytes differs from that of neuronal NMDA receptors, the effects of NAAG and NAA on them are unknown. We show that NAAG, but not NAA, evokes an inward membrane current in cerebellar white matter oligodendrocytes, which is reduced by NMDA receptor block (but not by block of metabotropic glutamate receptors). The size of the current evoked by NAAG, relative to that evoked by NMDA, was much smaller in oligodendrocytes than in neurons, and NAAG induced a rise in Ca2+i in neurons but not in oligodendrocytes. These differences in the effect of NAAG on oligodendrocytes and neurons may reflect the aforementioned difference in receptor subunit composition. In addition, as a major part of the response in oligodendrocytes was blocked by tetrodotoxin (TTX), much of the NAAG-evoked current in oligodendrocytes is a secondary consequence of activating neuronal NMDA receptors. Six hours exposure to 1 mM NAAG did not lead to the death of cells in the white matter. We conclude that an action of NAAG on oligodendrocyte NMDA receptors is unlikely to be a major contributor to white matter damage in the leucodystrophies.
The haemodynamic responses to neural activity that underlie the blood-oxygen-level-dependent (BOLD) signal used in functional magnetic resonance imaging (fMRI) of the brain are often assumed to be ...driven by energy use, particularly in presynaptic terminals or glia. However, recent work has suggested that most brain energy is used to power postsynaptic currents and action potentials rather than presynaptic or glial activity and, furthermore, that haemodynamic responses are driven by neurotransmitter-related signalling and not directly by the local energy needs of the brain. A firm understanding of the BOLD response will require investigation to be focussed on the neural signalling mechanisms controlling blood flow rather than on the locus of energy use.
What do the active areas on functional brain imaging pictures really indicate: brain energy use, neural spiking or synaptic activity?
Neural activity has been suggested to initially trigger ATP production by glycolysis, rather than oxidative phosphorylation, for three reasons: glycolytic enzymes are associated with ion pumps; ...neurons may increase their energy supply by activating glycolysis in astrocytes to generate lactate; and activity increases glucose uptake more than O₂ uptake. In rat hippocampal slices, neuronal activity rapidly decreased the levels of extracellular O₂ and intracellular NADH (reduced nicotinamide adenine dinucleotide), even with lactate dehydrogenase blocked to prevent lactate generation, or with only 20% superfused O₂ to mimic physiological O₂ levels. Pharmacological analysis revealed an energy budget in which 11% of O₂ use was on presynaptic action potentials, 17% was on presynaptic Ca²⁺ entry and transmitter release, 46% was on postsynaptic glutamate receptors, and 26% was on postsynaptic action potentials, in approximate accord with theoretical brain energy budgets. Thus, the major mechanisms mediating brain information processing are all initially powered by oxidative phosphorylation, and an astrocyte-neuron lactate shuttle is not needed for this to occur.
PDF
