This article by the Khakh lab characterizes the molecular and morphological features of astrocytes in 13 brain regions of the CNS, extending largely their previous study (Chai et al., 2017), where hippocampal and striatal astrocytes were thoroughly compared, including at the functional level.
The data generated will be a valuable resource for researchers studying astrocytes, providing extensive transcriptomics datasets as well as morphological parameters.
Surprisingly, Endo et al. show that the density of astrocytes across these 13 brain regions varies only by a factor of 2 and does not correlate with neuronal density. They also show variations of several metrics of astrocyte morphology, both within and between CNS regions. In fact, the most morphologically distinct astrocytes are found in the cerebellum, but this is probably due to the atypical morphology of Bergman glia, a specialized type of cerebellar glia.
Using advanced correlation analyses, Endo et al. identify modules of genes positively correlated to morphological features of astrocytes, which are mainly downregulated in neurodegenerative (ND) and psychiatric diseases. Indeed, astrocytes do display reduced territory in ND, as shown previously in a mouse model of AD (Olabarria et al., 2010) and replicated here in a different mouse model.
Then, they performed astrocyte-specific CRISPR knockdown of two genes encoding established cytoskeletal proteins (Fermt2 and Ezr) belonging to gene modules correlated with astrocyte morphological features. They show that this reduces astrocyte territory by 20 percent, altering memory, c-fos induction in neurons, and synapse number in the hippocampus.
Intriguingly, using scRNA-Seq, Endo et al. report the existence of seven sub-clusters of astrocytes in the cortex, striatum, and hippocampus, whose proportion differs slightly among these three regions and also in AD mice. It would now be interesting—but also very difficult, due to the lack of unique gene markers to identify these sub-clusters—to see whether specific sub-clusters are more prone to morphological alterations in disease.
This study further supports the idea that astrocyte morphology is key for their interactions with neurons (Pannasch et al., 2014; Stogsdill et al., 2017). It also shows that astrocytes are heterogeneous both within and between CNS regions, displaying subtle molecular and morphological specificities that require potent and dedicated techniques to evidence them. Future functional studies based on these rich datasets should provide insight into how astrocytes engage in region-specific interactions with neurons, through their finely controlled morphology.
References:
Chai H, Diaz-Castro B, Shigetomi E, Monte E, Octeau JC, Yu X, Cohn W, Rajendran PS, Vondriska TM, Whitelegge JP, Coppola G, Khakh BS.
Neural Circuit-Specialized Astrocytes: Transcriptomic, Proteomic, Morphological, and Functional Evidence.
Neuron. 2017 Aug 2;95(3):531-549.e9. Epub 2017 Jul 14
PubMed.
Olabarria M, Noristani HN, Verkhratsky A, Rodríguez JJ.
Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer's disease.
Glia. 2010 May;58(7):831-8.
PubMed.
Pannasch U, Freche D, Dallérac G, Ghézali G, Escartin C, Ezan P, Cohen-Salmon M, Benchenane K, Abudara V, Dufour A, Lübke JH, Déglon N, Knott G, Holcman D, Rouach N.
Connexin 30 sets synaptic strength by controlling astroglial synapse invasion.
Nat Neurosci. 2014 Apr;17(4):549-58. Epub 2014 Mar 2
PubMed.
Stogsdill JA, Ramirez J, Liu D, Kim YH, Baldwin KT, Enustun E, Ejikeme T, Ji RR, Eroglu C.
Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis.
Nature. 2017 Nov 8;551(7679):192-197.
PubMed.
Comments
UMR9199 Neurodegenerative Disease lab
This article by the Khakh lab characterizes the molecular and morphological features of astrocytes in 13 brain regions of the CNS, extending largely their previous study (Chai et al., 2017), where hippocampal and striatal astrocytes were thoroughly compared, including at the functional level.
The data generated will be a valuable resource for researchers studying astrocytes, providing extensive transcriptomics datasets as well as morphological parameters.
Surprisingly, Endo et al. show that the density of astrocytes across these 13 brain regions varies only by a factor of 2 and does not correlate with neuronal density. They also show variations of several metrics of astrocyte morphology, both within and between CNS regions. In fact, the most morphologically distinct astrocytes are found in the cerebellum, but this is probably due to the atypical morphology of Bergman glia, a specialized type of cerebellar glia.
Using advanced correlation analyses, Endo et al. identify modules of genes positively correlated to morphological features of astrocytes, which are mainly downregulated in neurodegenerative (ND) and psychiatric diseases. Indeed, astrocytes do display reduced territory in ND, as shown previously in a mouse model of AD (Olabarria et al., 2010) and replicated here in a different mouse model.
Then, they performed astrocyte-specific CRISPR knockdown of two genes encoding established cytoskeletal proteins (Fermt2 and Ezr) belonging to gene modules correlated with astrocyte morphological features. They show that this reduces astrocyte territory by 20 percent, altering memory, c-fos induction in neurons, and synapse number in the hippocampus.
Intriguingly, using scRNA-Seq, Endo et al. report the existence of seven sub-clusters of astrocytes in the cortex, striatum, and hippocampus, whose proportion differs slightly among these three regions and also in AD mice. It would now be interesting—but also very difficult, due to the lack of unique gene markers to identify these sub-clusters—to see whether specific sub-clusters are more prone to morphological alterations in disease.
This study further supports the idea that astrocyte morphology is key for their interactions with neurons (Pannasch et al., 2014; Stogsdill et al., 2017). It also shows that astrocytes are heterogeneous both within and between CNS regions, displaying subtle molecular and morphological specificities that require potent and dedicated techniques to evidence them. Future functional studies based on these rich datasets should provide insight into how astrocytes engage in region-specific interactions with neurons, through their finely controlled morphology.
References:
Chai H, Diaz-Castro B, Shigetomi E, Monte E, Octeau JC, Yu X, Cohn W, Rajendran PS, Vondriska TM, Whitelegge JP, Coppola G, Khakh BS. Neural Circuit-Specialized Astrocytes: Transcriptomic, Proteomic, Morphological, and Functional Evidence. Neuron. 2017 Aug 2;95(3):531-549.e9. Epub 2017 Jul 14 PubMed.
Olabarria M, Noristani HN, Verkhratsky A, Rodríguez JJ. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer's disease. Glia. 2010 May;58(7):831-8. PubMed.
Pannasch U, Freche D, Dallérac G, Ghézali G, Escartin C, Ezan P, Cohen-Salmon M, Benchenane K, Abudara V, Dufour A, Lübke JH, Déglon N, Knott G, Holcman D, Rouach N. Connexin 30 sets synaptic strength by controlling astroglial synapse invasion. Nat Neurosci. 2014 Apr;17(4):549-58. Epub 2014 Mar 2 PubMed.
Stogsdill JA, Ramirez J, Liu D, Kim YH, Baldwin KT, Enustun E, Ejikeme T, Ji RR, Eroglu C. Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis. Nature. 2017 Nov 8;551(7679):192-197. PubMed.
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