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      Astrocyte Dysfunctions and HIV-1 Neurotoxicity

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          Abstract

          Astrocytes play an important role in maintaining an optically suited milieu for neuronal functionality, and are involved in the progression and outcome of many neuropathological conditions. It becomes increasingly evident that astrocytes are significant contributors to HIV-1 associated neurological disorders by modulating the microenvironment in the central nervous system and releasing proinflammatory cytokines. Recent studies have revealed direct metabolic interactions between neurons and astrocytes observed particularly in HIV-1-associated neurological disorders by which astrocytic dysfunctions disregulate extracellular K+ homeostasis, intracellular calcium concentration, glutamate clearance, and blood brain barrier integrity and permeability. Such dysfunctions are amplified via gap junctions, directly or indirectly impacting surrounding neurons and significantly contributing to the pathogenesis of HIV-1-associated neuropathology. In this review, we tentatively address recent progresses on the roles astrocytes may play in HIV-1-associated neurotoxicity.

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          Most cited references74

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          Glutamate uptake.

          Brain tissue has a remarkable ability to accumulate glutamate. This ability is due to glutamate transporter proteins present in the plasma membranes of both glial cells and neurons. The transporter proteins represent the only (significant) mechanism for removal of glutamate from the extracellular fluid and their importance for the long-term maintenance of low and non-toxic concentrations of glutamate is now well documented. In addition to this simple, but essential glutamate removal role, the glutamate transporters appear to have more sophisticated functions in the modulation of neurotransmission. They may modify the time course of synaptic events, the extent and pattern of activation and desensitization of receptors outside the synaptic cleft and at neighboring synapses (intersynaptic cross-talk). Further, the glutamate transporters provide glutamate for synthesis of e.g. GABA, glutathione and protein, and for energy production. They also play roles in peripheral organs and tissues (e.g. bone, heart, intestine, kidneys, pancreas and placenta). Glutamate uptake appears to be modulated on virtually all possible levels, i.e. DNA transcription, mRNA splicing and degradation, protein synthesis and targeting, and actual amino acid transport activity and associated ion channel activities. A variety of soluble compounds (e.g. glutamate, cytokines and growth factors) influence glutamate transporter expression and activities. Neither the normal functioning of glutamatergic synapses nor the pathogenesis of major neurological diseases (e.g. cerebral ischemia, hypoglycemia, amyotrophic lateral sclerosis, Alzheimer's disease, traumatic brain injury, epilepsy and schizophrenia) as well as non-neurological diseases (e.g. osteoporosis) can be properly understood unless more is learned about these transporter proteins. Like glutamate itself, glutamate transporters are somehow involved in almost all aspects of normal and abnormal brain activity.
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            Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1.

            Extracellular levels of the excitatory neurotransmitter glutamate in the nervous system are maintained by transporters that actively remove glutamate from the extracellular space. Homozygous mice deficient in GLT-1, a widely distributed astrocytic glutamate transporter, show lethal spontaneous seizures and increased susceptibility to acute cortical injury. These effects can be attributed to elevated levels of residual glutamate in the brains of these mice.
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              Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling.

              The finding that astrocytes possess glutamate-sensitive ion channels hinted at a previously unrecognized signaling role for these cells. Now it is reported that cultured hippocampal astrocytes can respond to glutamate with a prompt and oscillatory elevation of cytoplasmic free calcium, visible through use of the fluorescent calcium indicator fluo-3. Two types of glutamate receptor--one preferring quisqualate and releasing calcium from intracellular stores and the other preferring kainate and promoting surface-membrane calcium influx--appear to be involved. Moreover, glutamate-induced increases in cytoplasmic free calcium frequently propagate as waves within the cytoplasm of individual astrocytes and between adjacent astrocytes in confluent cultures. These propagating waves of calcium suggest that networks of astrocytes may constitute a long-range signaling system within the brain.
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                Author and article information

                Journal
                101550222
                38935
                J AIDS Clin Res
                J AIDS Clin Res
                Journal of AIDS & clinical research
                2155-6113
                12 February 2014
                19 November 2013
                1 November 2013
                28 February 2014
                : 4
                : 11
                : 255
                Affiliations
                Neurophysiology Laboratory, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA
                Author notes
                [* ]Corresponding author: Huangui Xiong, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198- 5880, USA, Tel: 402-559-5140; Fax: 402-559-3744; hxiong@ 123456unmc.edu
                Article
                NIHMS554239
                10.4172/2155-6113.1000255
                3938291
                24587966
                d204af97-7ae5-4ca7-9411-61198b6dc131
                Copyright: © 2013 Ton H, et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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                Categories
                Article

                astrocytes,hiv-1 associated neurotoxicity,k+ channels,glutamate uptake,blood brain barrier,gap junctions

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