Brain Research Reviews最新文献

The main source of energy for the mammalian brain is glucose, and the main sink of energy in the mammalian brain is the neuron, so the conventional view of brain energy metabolism is that glucose is consumed preferentially in neurons. But between glucose and the production of energy are several steps that do not necessarily take place in the same cell. An alternative model has been proposed that states that glucose preferentially taken by astrocytes, is degraded to lactate and then exported into neurons to be oxidized. Short of definitive data, opinions about the relative merits of these competing models are divided, making it a very exciting field of research. Furthermore, growing evidence suggests that lactate acts as a signaling molecule, involved in Na⁺ sensing, glucosensing, and in coupling neuronal and glial activity to the modulation of vascular tone. In the present review, we discuss possible dynamics of glucose and lactate in excitatory synaptic regions, focusing on the transporters that catalyze the movement of these molecules.

The classical view of glial cells as simple supportive cells for neurons is being replaced by a new vision in which glial cells are active elements involved in the physiology of the nervous system. This new vision is based on the fact that astrocytes, a subtype of glial cells in the CNS, are stimulated by synaptically released neurotransmitters, which increase the astrocyte Ca²⁺ levels and stimulate the release of gliotransmitters that regulate synaptic efficacy and plasticity. Consequently, our understanding of synaptic function, previously thought to exclusively result from signaling between neurons, has also changed to include the bidirectional signaling between neurons and astrocytes. Hence, astrocytes have been revealed as integral elements involved in the synaptic physiology, therefore contributing to the processing, transfer and storage of information by the nervous system. Reciprocal communication between astrocytes and neurons is therefore part of the intercellular signaling processes involved in brain function.

Astrocytes have important functions in the metabolism of the brain. These cells provide neurons with metabolic substrates for energy production as well as with precursors for neurotransmitter and glutathione synthesis. Both the metabolism of astrocytes and the subsequent supply of metabolites from astrocytes to neurons are strongly affected by alterations in the cellular redox state. The cytosolic redox state of astrocytes depends predominantly on the ratios of the oxidised and reduced partners of the redox pairs NADH/NAD⁺, NADPH/NADP⁺ and GSH/GSSG. The NADH/NAD⁺ pair is predominately in the oxidised state to accept electrons that are produced during glycolysis. In contrast, the redox pairs NADPH/NADP⁺ and GSH/GSSG are biased towards the reduced state under unstressed conditions to provide electrons for reductive biosyntheses and antioxidative processes, respectively. In this review article we describe the metabolic processes that maintain the redox pairs in their desired redox states in the cytosol of astrocytes and discuss the consequences of alterations of the normal redox state for the regulation of cellular processes and for metabolite trafficking from astrocytes to neurons.

Like the liver or other peripheral organs, two regions of the adult brain possess the ability of self-renewal through a process called neurogenesis. This raises tremendous hope for repairing the damaged brain, and it has stimulated research on identifying signals controlling neurogenesis. Neurogenesis involves several stages from fate determination to synaptic integration via proliferation, migration, and maturation. While fate determination primarily depends on a genetic signature, other stages are controlled by the interplay between genes and microenvironmental signals. Here, we propose that neurotransmitters are master regulators of the different stages of neurogenesis. In favor of this idea, a description of selective neurotransmitter signaling and their functions in the largest neurogenic zone, the subventricular zone (SVZ), is provided. In particular, we emphasize the interactions between neuroblasts and astrocyte-like cells that release gamma-aminobutyric acid (GABA) and glutamate, respectively. However, we also raise several limitations to our knowledge on neurotransmitters in neurogenesis. The function of neurotransmitters in vivo remains largely unexplored. Neurotransmitter signaling has been viewed as uniform, which dramatically contrasts with the cellular and molecular mosaic nature of the SVZ. How neurotransmitters are integrated with other well-conserved molecules, such as sonic hedgehog, is poorly understood. In an effort to reconcile these differences, we discuss how specificity of neurotransmitter functions can be provided through their multitude of receptors and intracellular pathways in different cell types and their possible interactions with sonic hedgehog.

The tight spatial and temporal coupling between neuronal activity and blood flow ensures that active brain regions receive an adequate supply of oxygen and energetic metabolites. There clearly is still an enormous amount of experimental and theoretical work to be done to unravel the precise mechanism of neurovascular coupling, but over the last decade significant advances have been made. The most recent studies confirm the original finding that the activation of Ca²⁺ elevations in astrocyte endfeet is an essential step but also reveal new levels of complexity in the astrocyte control of neurovascular coupling. The recent evidence for a link between Ca²⁺ signalling in astrocytes and local metabolic states of the brain tissue has broad implications for the interpretation of data from functional brain imaging studies. Unraveling the full molecular mechanism of the astrocyte control of cerebral blood flow represents a formidable challenge in neurobiological research in the years to come that might also create opportunities for the development of new therapeutic strategies for cerebrovascular diseases such as ischemic stroke, hypertension and migraine as well as neurodegenerative diseases as Alzheimer's disease.

Astrocytes as a cell population are not well defined and comprise a heterogeneous population of cells. There are at least 9 different morphological variants which can coexist within one given brain region. Human astrocytes have a considerably more complex morphology as their rodent counterparts. There are also a number of functional differences depending on brain region and developmental stage in the normal (not pathologic) brain. Astrocytes can differ in functional gap junctional coupling, expression of transmitter receptors, membrane currents, and glutamate transporters. We feel that astrocyte heterogeneity has not yet been thoroughly explored and what we report here will just be a beginning of a new field of research.

The ability to investigate the electrophysiological properties of individual cells in acute brain tissue led to the discovery that many glial cells have the capacity to respond rapidly to neuronal activity. In particular, a distinct class of neuroglial cells known as NG2 cells, which exhibit many of the properties that have been described for glial subtypes such as complex cells, polydendrocytes, synantocytes and GluR cells, express ionotropic receptors for glutamate and GABA. In both gray and white matter, NG2 cells form direct synaptic junctions with axons, which enable transient activation of these receptors. Electrophysiological analyses have shown that these neuron-glia synapses exhibit all the hallmarks of ‘classical’ neuron-neuron synapses, including rapid activation, quantized responses, facilitation and depression, and presynaptic inhibition. Electron microscopy indicates that axons form morphologically distinct junctions at discrete sites along processes of NG2 cells, suggesting that NG2 cells are an overt target of axonal projections. AMPA receptors expressed by NG2 cells exhibit varying degrees of Ca²⁺ permeability, depending on the brain region and stage of development, and in white matter NG2 cells have also been shown to express functional NMDA receptors. Ca²⁺ influx through AMPA receptors following repetitive stimulation can trigger long term potentiation of synaptic currents in NG2 cells. The expression of receptors with significant Ca²⁺ permeability may increase the susceptibility of NG2 cells to excitotoxic injury. Future studies using transgenic mice in which expression of receptors can be manipulated selectively in NG2 cells have to define the functions of this enigmatic neuron-glia signaling in the normal and diseased CNS.

Synaptic neurotransmission at high temporal and spatial resolutions requires efficient removal and/or inactivation of presynaptically released transmitter to prevent spatial spreading of transmitter by diffusion and allow for fast termination of the postsynaptic response. This action must be carefully regulated to result in the fine tuning of inhibitory and excitatory neurotransmission, necessary for the proper processing of information in the central nervous system. At many synapses, high-affinity neurotransmitter transporters are responsible for transmitter deactivation by removing it from the synaptic cleft. The most prevailing neurotransmitters, glutamate, which mediates excitatory neurotransmission, as well as GABA and glycine, which act as inhibitory neurotransmitters, use these uptake systems. Neurotransmitter transporters have been found in both neuronal and glial cells, thus suggesting high cooperativity between these cell types in the control of extracellular transmitter concentrations. The generation and analysis of animals carrying targeted disruptions of transporter genes together with the use of selective inhibitors have allowed examining the contribution of individual transporter subtypes to synaptic transmission. This revealed the predominant role of glial expressed transporters in maintaining low extrasynaptic neurotransmitter levels. Additionally, transport activity has been shown to be actively regulated on both transcriptional and post-translational levels, which has important implications for synapse function under physiological and pathophysiological conditions. The analysis of these mechanisms will enhance not only our understanding of synapse function but will reveal new therapeutic strategies for the treatment of human neurological diseases.

The NG2 proteoglycan is a type 1-transmembrane protein expressed by a range of cell types within and outside the mammalian nervous system. NG2-expressing (NG2) cells are found in grey and white matter tracts of the developing and adult CNS and have previously been assumed to represent oligodendrocyte precursor cells: new work using transgenic mice has shown that NG2 cells generate oligodendrocytes, protoplasmic astrocytes and in some instances neurons in vivo. NG2 cells express GABAA receptors and the AMPA subtype of glutamate receptors. They make intimate contact to neurons prior to myelinating axons and also form electron-dense synaptic specialisations with axons in the cerebellum, cortex and hippocampus and with non-myelinated axons in the corpus callosum. These synaptic NG2 cells respond to neuronal release of glutamate and GABA. This neuron–glia interaction may thus regulate the differentiation and proliferation of NG2 cells. The C-terminal PDZ-binding motif of the NG2 protein binds several PDZ proteins including Mupp1, Syntenin and the Glutamate Receptor Interacting Protein (GRIP). Since GRIP can bind subunits of the AMPA receptors expressed by NG2 cells, the interaction between GRIP and NG2 may orientate the glial AMPA receptors towards sites of neuronal glutamate release. The origin, heterogeneity and function of NG2 cells as modulators of the neuronal network are important incompletely resolved questions.

One of the most intriguing discoveries during the last decade of developmental neurobiology is the fact that both in the developing and adult nervous system neural stem cells often turn out to have a glial identity: Radial glia generates neurons in the developing telencephalon of fish, birds and mammals and astro/radial glial stem cells in specialized neurogenic zones give rise to new neurons throughout life. What are the extrinsic signals acting on and the intrinsic signals acting within these glial populations endowing these with a neurogenic potential, whilst most other glia seemingly lack it? Studies on postnatal astroglia shed interesting light on this question as they are the intermediate between neurogenic radial glia and mature parenchymal astrocytes. At least in vitro their decision to acquire a glial fate is not yet irrevocable as forced expression of a single neurogenic transcription factor enables them to transgress their lineage and to give rise to fully functional neurons acquiring specific subtype characteristics. But even bona fide non-neurogenic glia in the adult nervous system can regain some of their radial glial heritage following injury as exemplified by reactive astroglia in the cerebral cortex and Müller glia in the retina. In this review first we will follow the direction of the physiological times' arrow, along which radial glia become transformed on one side into mature astrocytes gradually losing their neurogenic potential, while some of them seem to escape this dire destiny to settle in the few neurogenic oases of the adult brain where they generate neurons and glia throughout life. But we will also see how pathophysiological conditions partially can reverse the arrow of time reactivating the parenchymal astroglia to re-acquire some of the hallmarks of neural stem cells or progenitors. We will close this review with some thoughts on the surprising compatibility of the co-existence of a neural stem cell and glial identity within the very same cell from the perspective of the concept of transcriptional core networks.