Astrocytes play key roles in brain function and are extensively coupled via gap junctions, which are intercellular channels 'assumed' to facilitate relatively unrestricted transfer of molecules <1 kDa including glucose and its metabolites. However, studies of gap junction trafficking have relied on the transfer of fluorescent dyes and frequently equate dye transfer to the movement of endogenous molecules. In addition, previous studies with radiolabeled molecules did not account for intracellular metabolism of their tracers and therefore did not identify the actual molecules which trafficked through gap junctions. Although it is challenging to measure intercellular transfer of endogenous molecules directly, the impairment of the movement of these molecules through astrocytic syncytia in disease may help explain the etiology of CNS pathology. Therefore, the focus of our studies was to directly measure the transfer of specific glucose metabolites through the astrocytic syncytia to better understand the cellular basis of functional brain imaging, the role of astrocytic syncytia in diabetes, and the role of astrocytes in brain energy metabolism and nutrition such as astrocyte-to-neuron lactate shuttling.
Our findings demonstrate that astrocytic gap junction(s): (a) coupling is more extensive than previously reported and is continuous with the perivascular space even over long distances, (b) selectively restrict transfer of hexose-6-phosphates which were previously reported to be permeable, (c) traffic lactate and astrocytes minimally "shuttle" lactate to neighboring neurons in situ, and (d) are impaired by hyperglycemia in vitro and in situ which can be prevented and/or restored by treatment with chemical chaperones. Overall, these results expand our understanding of astrocytic gap junction coupling and permeability as well as the potential role of impaired astrocytic gap junction communication in hyperglycemia-induced neuropathologies in diabetes. Also, direct demonstration of low lactate "shuttling" from astrocytes-to-neurons challenges the paradigm that brain glucose metabolism is cellularly compartmentalized by linkage through extracellular shuttling of lactate from astrocytes-to-neurons.
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 70/04, Dissertation Abstracts International|
|Keywords:||Astrocytes, Brain, Diabetes, Functional imaging, Gap junctions, Metabolism|
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