One of the salient outcomes that could reshape our thinking about the role of astrocytes in AD is that calcium signaling alterations linked to dense-core plaque deposits extend beyond the spatial domain of the discrete histopathology, and can synchronize larger populations of astrocyte and astrocyte circuits, either through extracellular signaling or gap junctions. What that calcium is doing, its originating source, and how it affects neurophysiology has yet to be determined in these models.

Certainly, a strength of this study is the confirmation of cell type, as previous in-vivo studies have not done so with certainty and were claiming changes in neuronal calcium signaling, and may have largely been observing astrocytes or other cell types. A potential overinterpretation in this study is relying only on methoxy-X04 staining as an indicator of plaque presence, as this only stains insoluble, late-stage, dense-core deposits and not other perhaps more pathogenic forms such as oligomers and other soluble β amyloid species. In addition, it would be quite interesting to compare...  Read more

One of the salient outcomes that could reshape our thinking about the role of astrocytes in AD is that calcium signaling alterations linked to dense-core plaque deposits extend beyond the spatial domain of the discrete histopathology, and can synchronize larger populations of astrocyte and astrocyte circuits, either through extracellular signaling or gap junctions. What that calcium is doing, its originating source, and how it affects neurophysiology has yet to be determined in these models.

Certainly, a strength of this study is the confirmation of cell type, as previous in-vivo studies have not done so with certainty and were claiming changes in neuronal calcium signaling, and may have largely been observing astrocytes or other cell types. A potential overinterpretation in this study is relying only on methoxy-X04 staining as an indicator of plaque presence, as this only stains insoluble, late-stage, dense-core deposits and not other perhaps more pathogenic forms such as oligomers and other soluble β amyloid species. In addition, it would be quite interesting to compare calcium signaling differences between the APP and APP/PS1 mice.

View all comments by Grace (Beth) Stutzmann

Imaging calcium signals in neural structures like cortex are currently the only way to detect the activity of many or most neurons in a volume of tissue. Clay Reid in the Neurobiology Department at Harvard Medical School did this a while back and made important discoveries about the functioning of visual cortex. The current system, developed by Katsushi Arisaka, is a clever way to improve on the original method that Reid used. Basically, the idea is to use multiple lasers (four in this case) to make multiple (four here) simultaneous images. This lets you look over a larger volume of tissue or with better temporal resolution. This microscope is a technological tour de force and effectively pushes the limits of this approach.

I am confident that there will be important special uses for this instrument. There are several limitations of the two-photon microscope, however, and this advance improves on one of them (making a larger or faster image), but not on the other (maximum depth in cortex that can be studied is only about 0.4 mm, whereas the cortex is at least 1 mm thick)....  Read more

Imaging calcium signals in neural structures like cortex are currently the only way to detect the activity of many or most neurons in a volume of tissue. Clay Reid in the Neurobiology Department at Harvard Medical School did this a while back and made important discoveries about the functioning of visual cortex. The current system, developed by Katsushi Arisaka, is a clever way to improve on the original method that Reid used. Basically, the idea is to use multiple lasers (four in this case) to make multiple (four here) simultaneous images. This lets you look over a larger volume of tissue or with better temporal resolution. This microscope is a technological tour de force and effectively pushes the limits of this approach.

I am confident that there will be important special uses for this instrument. There are several limitations of the two-photon microscope, however, and this advance improves on one of them (making a larger or faster image), but not on the other (maximum depth in cortex that can be studied is only about 0.4 mm, whereas the cortex is at least 1 mm thick). Furthermore, although the fourfold speed increase is impressive, something like a 10-fold increase—or 100-fold—is what you really would want. So this is a wonderful technological achievement that will be important, but it is not a "game-changer."

View all comments by Charles Stevens

This is lovely technology with promise for future important biological studies and represents one of a series of technical improvements in multiphoton microscopy that allow deep imaging (e.g., with GRIN lenses) or use of awake, behaving animals. Along with the exciting new opticogenetic reagents, we are a step closer to being able to use optical tools to monitor neuronal activity in populations of neurons during normal behaviors and under disease conditions.

View all comments by Bradley Hyman

This is indeed a very interesting paper, as it shows how different astrocytes are compared to oligodendrocytes—the latter migrating far and compensating for any cells that are lost, while the former stay put both during development and in adulthood.

In regard to astrocyte-induced disease, these findings may be relevant, as death of astrocytes in a given domain cannot be compensated for. However, the ablation experiments occur very early and may be less relevant to age-related neurodegenerative diseases.

I think the biggest progress will be to understand the region-specific differences and specialization these cells have, and, hence, understand how they are specialized to support the neurons in their domain.

View all comments by Magdalena Goetz

This is one of the most interesting papers ever written on astrocytes. The implications are very important. Basically, it is showing that each domain of the brain has its own molecularly distinct type of astrocyte, and that these astrocytes respect their own unique boundaries. Most likely this is a very important design plan of the brain. It suggests distinct, domain-specific role(s) for astrocytes. Perhaps they are critical for specificity of axon guidance during development so appropriate neural circuit wiring occurs, as suggested by an earlier paper in Cell by David Anderson a few years ago (see Hochstim et al., 2008). Or perhaps they control domain-specific synapse formation, function, or plasticity. In addition, the paper also shows that killing of astrocytes in one domain results in a substantial decrease in excitatory synapse formation. A role for astrocytes in controlling synapse formation has so far mostly been shown in vitro, so it is very exciting to see evidence that astrocytes also have this role in vivo (see also...  Read more

This is one of the most interesting papers ever written on astrocytes. The implications are very important. Basically, it is showing that each domain of the brain has its own molecularly distinct type of astrocyte, and that these astrocytes respect their own unique boundaries. Most likely this is a very important design plan of the brain. It suggests distinct, domain-specific role(s) for astrocytes. Perhaps they are critical for specificity of axon guidance during development so appropriate neural circuit wiring occurs, as suggested by an earlier paper in Cell by David Anderson a few years ago (see Hochstim et al., 2008). Or perhaps they control domain-specific synapse formation, function, or plasticity. In addition, the paper also shows that killing of astrocytes in one domain results in a substantial decrease in excitatory synapse formation. A role for astrocytes in controlling synapse formation has so far mostly been shown in vitro, so it is very exciting to see evidence that astrocytes also have this role in vivo (see also previous work by Gabriel Corfas on the role of glia in synapse formation in the inner ear: also Rio et al., 2002).

This is a beautiful paper with many important implications, and it shows that we don't begin to understand the roles of astrocytes in normal development and function, and why so much glial heterogeneity is needed. There may be important implications for disease. Perhaps specific types of astrocytes malfunction or degenerate in disease situations. And, since astrocyte gene expression so closely resembles stem cells, perhaps domain-specific types of astrocytes can more easily be induced to become the type of neurons in that domain in order to repair/regenerate lost neuron types.

View all comments by Ben Barres