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Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D. Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron. 2009 Jun 25;62(6):788-801. PubMed.
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University of Arkansas for Medical Sciences
In an interview for a postdoctoral position in 1992, I presented my dissertation work on the calcium-destablizing effects of the glial protein S100B. The lab to which I had applied was focused on Alzheimer's disease, so I attempted to make my work relevant to their interests by highlighting the role of calcium in excitotoxicity. I was very nearly laughed off the dais by a senior scientist in the audience: "It's silly to think that excitotoxicity—a phenomenon that kills neurons within minutes to hours—could be involved in a neurodegenerative condition that progresses over years." At about the same time, Mark Mattson was beginning to publish his findings that excitotoxicity need not culminate in the death of the entire cell. His work showed that at lower concentrations or at shorter times, glutamate receptor agonists could cause pruning of dendrites only. Indeed, even subtler treatments would have the effect of simply slowing the outgrowth of dendrites. Thus, there came to be an appreciation of an overlap between glutamate's toxicity and its normal roles in development and plasticity. The former seemed to be almost an exaggeration of the latter.
Mark went on to show that the mechanisms by which excessive glutamate could have this limited impact on dendritic compartments (perhaps, single spines) include pathways formerly studied only in the field of apoptosis. Not only could excitotoxity be synapse-limited, but so could caspase-dependent "degeneration" (which would be better called "structural long-term depression, LTD"). If the biochemical changes manifest as long-term potentiation (LTP) can occasionally give rise to more lasting potentiations that are structural in nature, why couldn't synaptic depressions likewise make the transition from LTD to a structural change, i.e., removal of the synapse?
In addition to the claim that excitotoxicity is temporally inconsistent with AD, there is another caveat related to the effects of excessive glutamatergic stimulation which may be more difficult to shake. In AD, or any other in vivo setting, it has been argued that the efficiency of astrocytic transporters in clearing the synaptic cleft makes a glutamate elevation irrelevant if not impossible. Indeed, it is difficult to believe that Aβ could effect a dramatic change in synaptic glutamate levels by inhibiting neuronal transporters alone. Molecular biology approaches and pharmacology both point to astrocytic transporters as being nearly the whole story in clearing synapses of glutamate (Anderson et al, 2000). In the paper at hand, Li et al. present data suggesting that Aβ inhibits a neuronal glutamate transporter rather than astrocytic uptake (Figs. 5H and S3C). One of their arguments is that glutamate uptake into synaptosomes was inhibited by Aβ; however, synaptosomes are well known to contain astrocytic elements (Henn et al., 1976; Chicurel et al, 1993). Another point made by Li et al. is that DHK, an inhibitor of one of the "glial" glutamate transporters, created LTD that was distinct from that of Aβ’s. This is not definitive, however; one of the studies making a case for the significance of neuronal uptake demonstrates exquisite sensitivity of neuronal transporters to DHK (Wang et al., 1998). But reporting an inhibition of glial transporters by Aβ might have lacked sufficient novelty: Marni Harris showed this effect when she was a graduate student, almost 15 years ago (Harris et al., 1995)!
Finally, it is worth considering that the effects of Aβ on extracellular glutamate levels may not involve sodium-dependent transporters at all. Aβ can elicit glutamate release via the xc- transport system, a glutamate/cystine exchanger activated by oxidative stress. Although the effects of fibrillar Aβ on this system that we initially reported were modest (Barger & Basile, 2001), we have subsequently seen much larger increases with oligomeric preparations. This mechanism has relevance to the metabotropic glutamate receptor (mGluR) angle emphasized by Li et al. An important role for Group II mGluRs has been documented in the connection of xc- transport to cocaine relapse (Kau et al., 2008). The possible involvement of xc- transporters is perhaps more worthy of consideration given that almost all the data presented by Li et al. were obtained in tissue slices, where soluble agents applied to the bath can readily access glia at both extra- and intrasynaptic sites.
Anderson CM, Swanson RA. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia. 2000 Oct;32(1):1-14. PubMed.
Barger SW, Basile AS. Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function. J Neurochem. 2001 Feb;76(3):846-54. PubMed.
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Chicurel ME, Terrian DM, Potter H. mRNA at the synapse: analysis of a synaptosomal preparation enriched in hippocampal dendritic spines. J Neurosci. 1993 Sep;13(9):4054-63. PubMed.
Harris ME, Carney JM, Cole PS, Hensley K, Howard BJ, Martin L, Bummer P, Wang Y, Pedigo NW, Butterfield DA. beta-Amyloid peptide-derived, oxygen-dependent free radicals inhibit glutamate uptake in cultured astrocytes: implications for Alzheimer's disease. Neuroreport. 1995 Oct 2;6(14):1875-9. PubMed.
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Kau KS, Madayag A, Mantsch JR, Grier MD, Abdulhameed O, Baker DA. Blunted cystine-glutamate antiporter function in the nucleus accumbens promotes cocaine-induced drug seeking. Neuroscience. 2008 Aug 13;155(2):530-7. PubMed.
Wang GJ, Chung HJ, Schnuer J, Pratt K, Zable AC, Kavanaugh MP, Rosenberg PA. High affinity glutamate transport in rat cortical neurons in culture. Mol Pharmacol. 1998 Jan;53(1):88-96. PubMed.
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