Stargazing: Monitoring subcellular dynamics of brain astrocytes

Kacerovsky, J. Benjamin; Murai, Keith K.

doi:10.1016/j.neuroscience.2015.07.007

Cited by 33 publications

(26 citation statements)

References 131 publications

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“…A loss of small, distal processes may have special significance because distal processes that isolate synapses are responsible for extraneuronal ion and transmitter homeostasis. Their absence might severely alter neuronal excitability [12, 18]. Note that the double mutant AxD mice develop seizures at 4-5 weeks of age.…”

Section: Discussionmentioning

confidence: 99%

The origin of Rosenthal fibers and their contributions to astrocyte pathology in Alexander disease

Sosunov

McKhann

Goldman

2017

acta neuropathol commun

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Rosenthal fibers (RFs) are cytoplasmic, proteinaceous aggregates. They are the pathognomonic feature of the astrocyte pathology in Alexander Disease (AxD), a neurodegenerative disorder caused by heterozygous mutations in the GFAP gene, encoding glial fibrillary acidic protein (GFAP). Although RFs have been known for many years their origin and significance remain elusive issues. We have used mouse models of AxD based on the overexpression of human GFAP (transgenic, TG) and a point mutation in mouse GFAP (knock-in, KI) to examine the formation of RFs and to find astrocyte changes that correlate with the appearance of RFs. We found RFs of various sizes and shapes. The smallest ones appear as granular depositions on intermediate filaments. These contain GFAP and the small heat shock protein, alphaB-crystallin. Their aggregation appears to give rise to large RFs. The appearance of new RFs and the growth of previously formed RFs occur over time. We determined that DAPI is a reliable marker of RFs and in parallel with Fluoro-Jade B (FJB) staining defined a high variability in the appearance of RFs, even in neighboring astrocytes. Although many astrocytes in AxD with increased levels of GFAP and with or without RFs change their phenotype, only some cells with large numbers of RFs show a profound reconstruction of cellular processes, with a loss of fine distal processes and the appearance of large, lobulated nuclei, likely due to arrested mitosis. We conclude that 1) RFs appear to originate as small, osmiophilic masses containing both GFAP and alphaB-crystallin deposited on bundles of intermediate filaments. 2) RFs continue to form within AxD astrocytes over time. 3) DAPI is a reliable marker for RFs and can be used with immunolabeling. 4) RFs appear to interfere with the successful completion of astrocyte mitosis and cell division.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0425-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The origin of Rosenthal fibers and their contributions to astrocyte pathology in Alexander disease

Sosunov

McKhann

Goldman

2017

acta neuropathol commun

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“…The smallest of these processes, sometimes called the peripheral astrocytic processes or fine processes may be only 20–200 nm in diameter and possess very little cytoplasm (for review, see Benjamin Kacerovsky and Murai, 2015). While GLT-1 (GLAST, glutamine synthetase, Na + /K + -ATPase, etc) have been localized to the fine processes of astrocytes (Chaudhry et al, 1995; Cholet et al, 2002; Norenberg and Martinez-Hernandez, 1979), there was a general belief that mitochondria were too large to fit into these fine processes (in many other cells mitochondria are 1 μm in diameter or larger).…”

Section: Coupling Of Glutamate Transport To Mitochondriamentioning

confidence: 99%

“…In this same system, we have monitored the movement of tips of astrocytic processes and mitochondria over a 24 hour period of time using confocal microscopy and noted that mitochondria are frequently found at the tips of mobile processes (O’Donnell and Robinson, unpublished observations). Using electroporation to sparsely label astrocytic mitochondria in vivo , mitochondria are observed throughout the astrocyte including distal processes and vascular endfeet (Benjamin Kacerovsky and Murai, 2015). Together these studies provide compelling evidence that mitochondria are found throughout the astrocyte processes.…”

Section: Coupling Of Glutamate Transport To Mitochondriamentioning

confidence: 99%

Astroglial glutamate transporters coordinate excitatory signaling and brain energetics

Robinson

Jackson

2016

Neurochemistry International

137

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In the mammalian brain, a family of sodium-dependent transporters maintains low extracellular glutamate and shapes excitatory signaling. The bulk of this activity is mediated by the astroglial glutamate transporters GLT-1 and GLAST (also called EAAT2 and EAAT1). In this review, we will discuss evidence that these transporters co-localize with, form physical (co-immunoprecipitable) interactions with, and functionally couple to various ‘energy-generating’ systems, including the Na+/K+-ATPase, the Na+/Ca2+ exchanger, glycogen metabolizing enzymes, glycolytic enzymes, and mitochondria/mitochondrial proteins. This functional coupling is bidirectional with many of these systems both being regulated by glutamate transport and providing the ‘fuel’ to support glutamate uptake. Given the importance of glutamate uptake to maintaining synaptic signaling and preventing excitotoxicity, it should not be surprising that some of these systems appear to ‘redundantly’ support the energetic costs of glutamate uptake. Although the glutamate-glutamine cycle contributes to recycling of neurotransmitter pools of glutamate, this is an over-simplification. The ramifications of co-compartmentalization of glutamate transporters with mitochondria for glutamate metabolism are discussed. Energy consumption in the brain accounts for ~20% of the basal metabolic rate and relies almost exclusively on glucose for the production of ATP. However, the brain does not possess substantial reserves of glucose or other fuels. To ensure adequate energetic supply, increases in neuronal activity are matched by increases in cerebral blood flow via a process known as ‘neurovascular coupling’. While the mechanisms for this coupling are not completely resolved, it is generally agreed that astrocytes, with processes that extend to synapses and endfeet that surround blood vessels, mediate at least some of the signal that causes vasodilation. Several studies have shown that either genetic deletion or pharmacologic inhibition of glutamate transport impairs neurovascular coupling. Together these studies strongly suggest that glutamate transport not only coordinates excitatory signaling, but also plays a pivotal role in regulating brain energetics.

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“…( b) , ventral views of tdTomato fluorescence clearly revealed single glial cells within the VGL underlying the SON. Most notable was the fact that, in addition to a clearly defined soma, many of these cells featured a large cloud of diffuse fluorescence resembling the highly complex network of protoplasmic processes observed in astrocytes from other brain regions (27 out of 77 cells examined, four SONs from two mice (Fig. b , c ).…”

Section: Resultsmentioning

confidence: 90%

Effects of Salt Loading on the Morphology of Astrocytes in the Ventral Glia Limitans of the Rat Supraoptic Nucleus

Choe

Prager‐Khoutorsky

Farmer

et al. 2016

J Neuroendocrinology

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In the ventral glial limitans (VGL) of the supraoptic nucleus (SON) of the rat, a unique astrocyte type is found with an ability to undergo striking morphological plasticity in response to a wide range of physiological stimulations such as chronic hypernatraemia. This includes a thinning of the VGL, which contains the somata and proximal processes of these astrocytes, as well as an almost complete withdrawal of their vertically-oriented distal processes. Currently, there is little information available on the types of astrocytes that reside in the SON-VGL and which of these exhibit state-dependent structural plasticity. To address this, we enabled the visualisation of single SON-VGL glia using two novel cell labelling techniques with fluorescence microscopy. First, we used an inducible genetic reporter mouse line that allowed the specific labelling of a low density of astrocytes expressing glutamate and aspartate transporter (GLAST)/excitatory amino acid transporter 1. This approach revealed a high degree of variability in the morphology of mouse SON-VGL astrocytes, in contrast to what has been reported for cortical astrocytes. Next, we used the DiOlistlic labelling approach to label single glial cells with DiI in the SON-VGL of rats. Astrocytes observed using this approach shared the morphological features of GLAST-expressing astrocytes in the mouse SON-VGL. Specific structural aspects of these cells were modified by chronic hypernatraemia achieved by 7-day salt loading. Notably, the average area of cells exhibiting protoplasmic features was significantly reduced in the horizontal plane, and the size of varicosities present on fibrous projections was significantly enlarged. These observations indicate that novel cell labelling methods can significantly advance our understanding of SON-VGL cells and reveal specific forms of morphological plasticity that can be driven by chronic hypernatraemia.

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Stargazing: Monitoring subcellular dynamics of brain astrocytes

Cited by 33 publications

References 131 publications

The origin of Rosenthal fibers and their contributions to astrocyte pathology in Alexander disease

The origin of Rosenthal fibers and their contributions to astrocyte pathology in Alexander disease

Astroglial glutamate transporters coordinate excitatory signaling and brain energetics

Effects of Salt Loading on the Morphology of Astrocytes in the Ventral Glia Limitans of the Rat Supraoptic Nucleus

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