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• W2756641845 abstract "Anatomy, physiology, proteomics, and genomics reveal the prospect of distinct highly specialized astrocyte subtypes within neural circuits. Anatomy, physiology, proteomics, and genomics reveal the prospect of distinct highly specialized astrocyte subtypes within neural circuits. Within the mammalian central nervous system (CNS), it is unanimously agreed that numerous distinct neuronal subtypes exist, each specialized to carry out particular functions for information processing. In striking contrast to this is the notion that astrocytes, a glial cell subtype, are identical and interchangeable throughout the CNS. In an article in Neuron, Chai et al., 2017Chai H. Diaz-Castro B. Shigetomi E. Monte E. Octeau J.C. Yu X. Cohn W. Rajendran P.S. Vondriska T.M. Whitelegge J.P. et al.Neuron. 2017; 95: 531-549Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar challenge this belief by extensively comparing the genetics and physiology of striatal and hippocampal astrocytes. The authors identified unanticipated anatomical, electrophysiological, and genetic differences in astrocytic form and function, suggesting that astrocytes are not generic but specialized within distinct neural circuits. Moreover, unraveling circuit-specific astrocytic properties may be useful for targeting pathological brain conditions. The study of astrocytes has become a rapidly progressing field of research in neuroscience over the last 30 years. In the human forebrain, ∼20% of all cells are astrocytes, and in the mammalian cerebral cortex, the number of astrocytes may exceed that of neurons (Khakh and Sofroniew, 2015Khakh B.S. Sofroniew M.V. Nat. Neurosci. 2015; 18: 942-952Crossref PubMed Scopus (651) Google Scholar). Despite these facts, we are just starting to scratch the surface of astrocytic functions and diversity. Originally thought as mere connective tissue of the brain, astrocytes are now known to participate in all essential CNS functions, including synaptic plasticity, neurotransmitter clearance, extracellular water and ion homeostasis, providing cerebrovascular control, and clearing metabolic waste products (Iliff et al., 2012Iliff J.J. Wang M. Liao Y. Plogg B.A. Peng W. Gundersen G.A. Benveniste H. Vates G.E. Deane R. Goldman S.A. et al.Sci. Transl. Med. 2012; 4: 147ra111Crossref PubMed Scopus (2621) Google Scholar, Khakh and Sofroniew, 2015Khakh B.S. Sofroniew M.V. Nat. Neurosci. 2015; 18: 942-952Crossref PubMed Scopus (651) Google Scholar). Furthermore, astrocytes regulate neural network activity patterns and oscillations (Poskanzer and Yuste, 2016Poskanzer K.E. Yuste R. Proc. Natl. Acad. Sci. USA. 2016; 113: E2675-E2684Crossref PubMed Scopus (204) Google Scholar), intriguingly implicating them in neural circuit dynamics and computations. A hallmark of astrocytes is their high degree of intercellular communication through gap-junction channels formed, predominantly, by connexin proteins, allowing long-range exchange of ions, metabolites, as well as their sensitivity to neuromodulators that mediate brain-wide signaling (Bennett et al., 2012Bennett M.V.L. Garré J.M. Orellana J.A. Bukauskas F.F. Nedergaard M. Sáez J.C. Brain Res. 2012; 1487: 3-15Crossref PubMed Scopus (159) Google Scholar). Finally, the morphology of astrocytes is highly complex, and their branched processes are, to a large extent, what allows each astrocyte to communicate with many neurons simultaneously (Khakh and Sofroniew, 2015Khakh B.S. Sofroniew M.V. Nat. Neurosci. 2015; 18: 942-952Crossref PubMed Scopus (651) Google Scholar). These properties position astrocytes optimally for orchestrating neural circuit activity and for shaping neural signaling. The close structural and functional relationship between neurons and astrocytes has been demonstrated at several organizational levels, but astrocytic functionality was generally considered well conserved across the brain. While a number of studies have documented the vast heterogeneity of Ca2+ signaling that occurs within single astrocytic processes, Chai et al., 2017Chai H. Diaz-Castro B. Shigetomi E. Monte E. Octeau J.C. Yu X. Cohn W. Rajendran P.S. Vondriska T.M. Whitelegge J.P. et al.Neuron. 2017; 95: 531-549Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar extend this finding to population diversity in Ca2+ signaling mechanisms. Locally arranged astrocytes within a specific circuit may display variable levels and types of ion channels and surface receptors from their close neighbors and, thus, may have subtle differences in signaling properties and respond differentially to the on-going neural activity within the circuit they regulate. What’s more, while both striatal and hippocampal astrocytes are likely to express Gq-, Gi-, and Gs-coupled metabotropic receptors, only Gq receptor activation was found to evoke robust Ca2+ activity in hippocampal astrocytes (Figure 1). This finding suggests that it may not be possible to predict the consequential astrocytic Ca2+ response based solely on receptor expression and that fundamental Ca2+ mobilization mechanisms in astrocytes may differ in a brain area specific manner. It will be important for future studies to examine the full complexity of astrocytic Ca2+ signaling, believed to be the core currency of astrocyte signaling, in vivo in different brain areas. Chai et al., 2017Chai H. Diaz-Castro B. Shigetomi E. Monte E. Octeau J.C. Yu X. Cohn W. Rajendran P.S. Vondriska T.M. Whitelegge J.P. et al.Neuron. 2017; 95: 531-549Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar interrogates the idea that astrocytes may be tailored and differentially specialized to meet the demands of specific neural circuits. For example, whereas hippocampal astrocytes are labeled with antibodies for glial fibrillary acidic protein (GFAP), very minor labeling of striatal astrocytes occurred when targeting this commonly used marker. Fascinatingly, the authors also observed much tighter interaction between hippocampal astrocytes and excitatory synapses than was the case for striatal astrocytes (Figure 1). As dendritic spine dynamics and synaptic signaling are fundamental in shaping neural input-output transformations, synaptic plasticity, and local circuit activity, it would be important to consider fully the association of dendritic spines with their local astrocytic process when investigating structural and functional changes in neuronal processes, for example, as occurs during long-term potentiation or depression. Given that the striatum is primarily composed of GABAergic interneurons, it is intriguing to speculate that this association reflects the underlying composition of the neural circuit, and, for example, reflects the differential need for tight regulation of extracellular K+ levels. This further reinforces that specialized astrocytes may have developed in areas, such as the hippocampus, to optimally support the unique functions of that particular brain area. Gene classes in hippocampal astrocytes are associated preferentially with neurogenesis, and a recent study found that astrocytes play a central role in regulating the synaptic integration of adult-born hippocampal neurons (Sultan et al., 2015Sultan S. Li L. Moss J. Petrelli F. Cassé F. Gebara E. Lopatar J. Pfrieger F.W. Bezzi P. Bischofberger J. Toni N. Neuron. 2015; 88: 957-972Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar). Thus, astrocytic dysfunction may result in impaired adult neurogenesis and cognitive deficits as a consequence. Interestingly, in Alexander’s disease, mutation of GFAP in astrocytes results in impaired adult neurogenesis and learning (Hagemann et al., 2013Hagemann T.L. Paylor R. Messing A. J. Neurosci. 2013; 33: 18698-18706Crossref PubMed Scopus (38) Google Scholar). In the future, it would be valuable to determine if astrocytic regulation of neurogenesis is similarly compromised in other neurodegenerative disorders, such as Alzheimer’s disease. On a more fundamental level, the neurogenic hippocampal area, the dentate gyrus, has been implicated as a key player in the brain’s capacity to distinguish between memories that closely resemble each other by generating non-overlapping memory representations (Berron et al., 2016Berron D. Schütze H. Maass A. Cardenas-Blanco A. Kuijf H.J. Kumaran D. Düzel E. J. Neurosci. 2016; 36: 7569-7579Crossref PubMed Scopus (135) Google Scholar). Given the salient position of astrocytes in integrating and regulating many thousands of hippocampal synapses simultaneously in both time and space, it would be truly appealing to elucidate the putative role of dentate gyrus astrocytes in the fundamental properties of spatial memory and learning processes. Genetic profile differences in astrocytes may precipitate divergence in critical astrocytic functions, and Chai et al., 2017Chai H. Diaz-Castro B. Shigetomi E. Monte E. Octeau J.C. Yu X. Cohn W. Rajendran P.S. Vondriska T.M. Whitelegge J.P. et al.Neuron. 2017; 95: 531-549Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar identify differences in K+-permeable channels and gap-junctional coupling between hippocampal and striatal astrocytes. This compliments results from studies in the spinal cord, where astrocytes were found to have 10-fold less expression of the glutamate transporter, GLT-1, than in the brain, resulting in decreased glutamate uptake (Regan et al., 2007Regan M.R. Huang Y.H. Kim Y.S. Dykes-Hoberg M.I. Jin L. Watkins A.M. Bergles D.E. Rothstein J.D. J. Neurosci. 2007; 27: 6607-6619Crossref PubMed Scopus (257) Google Scholar). The results by Chai et al., 2017Chai H. Diaz-Castro B. Shigetomi E. Monte E. Octeau J.C. Yu X. Cohn W. Rajendran P.S. Vondriska T.M. Whitelegge J.P. et al.Neuron. 2017; 95: 531-549Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar also contribute new important information toward understanding the unresolved inconsistencies between previous studies in the field. In particular, little evidence for vesicular glutamate release from astrocytes (a mechanism termed gliotransmission) was identified in the present study, highlighting the central importance of considering the physiological context of the model under investigation when interpreting and generalizing experimental findings. An interesting observation made by Chai et al., 2017Chai H. Diaz-Castro B. Shigetomi E. Monte E. Octeau J.C. Yu X. Cohn W. Rajendran P.S. Vondriska T.M. Whitelegge J.P. et al.Neuron. 2017; 95: 531-549Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar is that specific populations of astrocytes, specifically in the striatum, may be salient in the pathophysiology of Huntington’s disease (HD). Astrocytes are known to be radically altered in HD (Benraiss et al., 2016Benraiss A. Wang S. Herrlinger S. Li X. Chandler-Militello D. Mauceri J. Burm H.B. Toner M. Osipovitch M. Jim Xu Q. et al.Nat. Commun. 2016; 7: 11758Crossref PubMed Scopus (111) Google Scholar), and through the identification of striatal-specific astrocytic-expression of the thyroid hormone-binding protein μ-crystallin, the authors link selective astrocyte dysfunction with the altered levels of μ-crystallin found in human and mouse models of HD. Preservation of normal healthy astrocytic function may well be the battleground on which the war for beating brain disease is fought. Overall, astrocytes may now be regarded as both morphologically and functionally distinct, and as such, the unique aspects of astrocytes may now provide fresh insight into the competencies of the mammalian brain. Better understanding of how differential astrocytic function contributes to neural circuit processing is a key question for the future. Such insights may pave the way forward for future development of drug targets and combating neurological diseases that cause a grave decline in the quality of life." @default.
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• W2756641845 title "Astrocytes: Tailored to Support the Demand of Neural Circuits?" @default.
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