Abstract:Intercellular calcium waves in central nervous system astrocyte networks underline the principle mechanism of cell signaling in astrocyte syncsytiums, which putatively contribute to the modulation of neuronal signaling and metabolic regulation. In support of carrying out systems level analyses of astrocyte networks, we have optimized and validated the converging squares image segmentation algorithm to automatically detect the relative spatial locations of all cells in a visible network as a preliminary step to… Show more
“…One of the functions of NAAG is that of a dynamic neurotransmitter, specifically targeted to the astrocytic surface metabotropic glutamate receptor 3 (GRM3), activation of which initiates intracellular calcium transients [22] and secondary astrocyte-astrocyte and astrocyte-vascular system signals that increase focal blood flow [23,24]. A timely increase in focal blood perfusion is necessary in order to remove neuronal waste products including metabolic water, and to rapidly supply additional energy and oxygen as needed in response to neurostimulation.…”
Section: Naa and Naag Are Released To Ecf By Stimulated Neuronsmentioning
Canavan disease (CD) is a genetic degenerative brain disorder associated with mutations of the gene encoding aspartoacylase (ASPA). In humans, the CD syndrome is marked by early onset, hydrocephalus, macroencephaly, psychomotor retardation, and spongiform myelin sheath vacuolization with progressive leukodystrophy. Metabolic hallmarks of the disease include elevated N-acetylaspartate (NAA) levels in brain, plasma and CSF, along with daily excretion of large amounts of NAA and its anabolic metabolite, N-acetylaspartylglutamate (NAAG). Of the observed neuropathies, the most important appears to be the extensive demyelination that interferes with normal neuronal signaling. However, finding the links between the lacks of ASPA activity in oligodendrocytes, the buildup of NAA in white matter (WM) and the mechanisms underlying the edematous spongiform leukodystrophy have remained elusive. In this analytical review we consider what those links might be and propose that in CD, the pathological buildup of NAA in limited WM extracellular fluid (ECF) is responsible for increased ECF osmotic-hydrostatic pressure and initiation of the demyelination process. We also hypothesize that NAA is not directly liberated by neurons in WM as it is in gray matter, and that its source in WM ECF is solely as a product of the catabolism of axon-released NAAG at nodes of Ranvier by astrocyte NAAG peptidase after it has docked with the astrocyte surface metabotropic glutamate receptor 3. This hypothesis ascribes for the first time a possible key role played by astrocytes in CD, linking the lack of ASPA activity in myelinating oligodendrocytes, the pathological buildup of NAA in WM ECF, and the spongiform demyelination process. It also offers new perspectives on the cause of the leukodystrophy in CD, and on possible treatment strategies for this inherited metabolic disease.
“…One of the functions of NAAG is that of a dynamic neurotransmitter, specifically targeted to the astrocytic surface metabotropic glutamate receptor 3 (GRM3), activation of which initiates intracellular calcium transients [22] and secondary astrocyte-astrocyte and astrocyte-vascular system signals that increase focal blood flow [23,24]. A timely increase in focal blood perfusion is necessary in order to remove neuronal waste products including metabolic water, and to rapidly supply additional energy and oxygen as needed in response to neurostimulation.…”
Section: Naa and Naag Are Released To Ecf By Stimulated Neuronsmentioning
Canavan disease (CD) is a genetic degenerative brain disorder associated with mutations of the gene encoding aspartoacylase (ASPA). In humans, the CD syndrome is marked by early onset, hydrocephalus, macroencephaly, psychomotor retardation, and spongiform myelin sheath vacuolization with progressive leukodystrophy. Metabolic hallmarks of the disease include elevated N-acetylaspartate (NAA) levels in brain, plasma and CSF, along with daily excretion of large amounts of NAA and its anabolic metabolite, N-acetylaspartylglutamate (NAAG). Of the observed neuropathies, the most important appears to be the extensive demyelination that interferes with normal neuronal signaling. However, finding the links between the lacks of ASPA activity in oligodendrocytes, the buildup of NAA in white matter (WM) and the mechanisms underlying the edematous spongiform leukodystrophy have remained elusive. In this analytical review we consider what those links might be and propose that in CD, the pathological buildup of NAA in limited WM extracellular fluid (ECF) is responsible for increased ECF osmotic-hydrostatic pressure and initiation of the demyelination process. We also hypothesize that NAA is not directly liberated by neurons in WM as it is in gray matter, and that its source in WM ECF is solely as a product of the catabolism of axon-released NAAG at nodes of Ranvier by astrocyte NAAG peptidase after it has docked with the astrocyte surface metabotropic glutamate receptor 3. This hypothesis ascribes for the first time a possible key role played by astrocytes in CD, linking the lack of ASPA activity in myelinating oligodendrocytes, the pathological buildup of NAA in WM ECF, and the spongiform demyelination process. It also offers new perspectives on the cause of the leukodystrophy in CD, and on possible treatment strategies for this inherited metabolic disease.
“…81) Online signal processing is also important in fMCI studies. Several studies proposed automatic signal processing algorithms to select the regions of interest 19,82,83) and to detect spike events from time series of a calcium trace. 18,25,84) Realtime closed-loop systems 85) are useful for further development of online analyses, such as experiments with eventdriven stimulation.…”
Section: Fmci Application In Brain Slicesmentioning
“…Benesova et al (2009) employed edge-detection algorithms for computing GFAP+ cell areas, followed by manual selection of astrocyte soma. One of the first automated methods was presented by Hashemi et al (2008). Their method is based on the converging squares algorithm for analyzing intracellular signaling in astrocytes.…”
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