Inhibitory Input Directs Astrocyte Morphogenesis Through Glial GABA R

Overview

Journal bioRxiv

Date 2023 Mar 30

PMID 36993256

Authors

Yi-Ting Cheng

Estefania Luna-Figueroa

Junsung Woo

Hsiao-Chi Chen

Zhung-Fu Lee

Akdes Serin Harmanci

Benjamin Deneen

Affiliations

Soon will be listed here.

Abstract

Communication between neurons and glia plays an important role in establishing and maintaining higher order brain function. Astrocytes are endowed with complex morphologies which places their peripheral processes in close proximity to neuronal synapses and directly contributes to their regulation of brain circuits. Recent studies have shown that excitatory neuronal activity promotes oligodendrocyte differentiation; whether inhibitory neurotransmission regulates astrocyte morphogenesis during development is unknown. Here we show that inhibitory neuron activity is necessary and sufficient for astrocyte morphogenesis. We found that input from inhibitory neurons functions through astrocytic GABA R and that its deletion in astrocytes results in a loss of morphological complexity across a host of brain regions and disruption of circuit function. Expression of GABA R in developing astrocytes is regulated in a region-specific manner by SOX9 or NFIA and deletion of these transcription factors results in region-specific defects in astrocyte morphogenesis, which is conferred by interactions with transcription factors exhibiting region-restricted patterns of expression. Together our studies identify input from inhibitory neurons and astrocytic GABA R as universal regulators of morphogenesis, while further revealing a combinatorial code of region-specific transcriptional dependencies for astrocyte development that is intertwined with activity-dependent processes.

References

Anthony T, Heintz N . The folate metabolic enzyme ALDH1L1 is restricted to the midline of the early CNS, suggesting a role in human neural tube defects. J Comp Neurol. 2006; 500(2):368-83. DOI: 10.1002/cne.21179. View

Stolt C, Lommes P, Sock E, Chaboissier M, Schedl A, Wegner M . The Sox9 transcription factor determines glial fate choice in the developing spinal cord. Genes Dev. 2003; 17(13):1677-89. PMC: 196138. DOI: 10.1101/gad.259003. View

Hao Y, Hao S, Andersen-Nissen E, Mauck 3rd W, Zheng S, Butler A . Integrated analysis of multimodal single-cell data. Cell. 2021; 184(13):3573-3587.e29. PMC: 8238499. DOI: 10.1016/j.cell.2021.04.048. View

Subramanian L, Sarkar A, Shetty A, Muralidharan B, Padmanabhan H, Piper M . Transcription factor Lhx2 is necessary and sufficient to suppress astrogliogenesis and promote neurogenesis in the developing hippocampus. Proc Natl Acad Sci U S A. 2011; 108(27):E265-74. PMC: 3131330. DOI: 10.1073/pnas.1101109108. View

Osso L, Rankin K, Chan J . Experience-dependent myelination following stress is mediated by the neuropeptide dynorphin. Neuron. 2021; 109(22):3619-3632.e5. PMC: 8602781. DOI: 10.1016/j.neuron.2021.08.015. View

Ung K, Huang T, Lozzi B, Woo J, Hanson E, Pekarek B . Olfactory bulb astrocytes mediate sensory circuit processing through Sox9 in the mouse brain. Nat Commun. 2021; 12(1):5230. PMC: 8410770. DOI: 10.1038/s41467-021-25444-3. View

Koyama Y, Yoshioka Y, Hashimoto H, Matsuda T, Baba A . Endothelins increase tyrosine phosphorylation of astrocytic focal adhesion kinase and paxillin accompanied by their association with cytoskeletal components. Neuroscience. 2000; 101(1):219-27. DOI: 10.1016/s0306-4522(00)00330-4. View

Aran D, Looney A, Liu L, Wu E, Fong V, Hsu A . Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol. 2019; 20(2):163-172. PMC: 6340744. DOI: 10.1038/s41590-018-0276-y. View

Wu C, Sun D . GABA receptors in brain development, function, and injury. Metab Brain Dis. 2014; 30(2):367-79. PMC: 4231020. DOI: 10.1007/s11011-014-9560-1. View

10.

Volterra A, Meldolesi J . Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci. 2005; 6(8):626-40. DOI: 10.1038/nrn1722. View

11.

Seifert G, Schilling K, Steinhauser C . Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci. 2006; 7(3):194-206. DOI: 10.1038/nrn1870. View

12.

Akiyama H, Chaboissier M, Martin J, Schedl A, de Crombrugghe B . The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. 2002; 16(21):2813-28. PMC: 187468. DOI: 10.1101/gad.1017802. View

13.

Stogsdill J, Ramirez J, Liu D, Kim Y, Baldwin K, Enustun E . Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis. Nature. 2017; 551(7679):192-197. PMC: 5796651. DOI: 10.1038/nature24638. View

14.

Lin C, Yu K, Hatcher A, Huang T, Lee H, Carlson J . Identification of diverse astrocyte populations and their malignant analogs. Nat Neurosci. 2017; 20(3):396-405. PMC: 5824716. DOI: 10.1038/nn.4493. View

15.

Srinivasan R, Lu T, Chai H, Xu J, Huang B, Golshani P . New Transgenic Mouse Lines for Selectively Targeting Astrocytes and Studying Calcium Signals in Astrocyte Processes In Situ and In Vivo. Neuron. 2016; 92(6):1181-1195. PMC: 5403514. DOI: 10.1016/j.neuron.2016.11.030. View

16.

Farhy-Tselnicker I, Boisvert M, Liu H, Dowling C, Erikson G, Blanco-Suarez E . Activity-dependent modulation of synapse-regulating genes in astrocytes. Elife. 2021; 10. PMC: 8497060. DOI: 10.7554/eLife.70514. View

17.

Mariotti L, Losi G, Sessolo M, Marcon I, Carmignoto G . The inhibitory neurotransmitter GABA evokes long-lasting Ca(2+) oscillations in cortical astrocytes. Glia. 2015; 64(3):363-73. PMC: 5057345. DOI: 10.1002/glia.22933. View

18.

Deneen B, Ho R, Lukaszewicz A, Hochstim C, Gronostajski R, Anderson D . The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord. Neuron. 2006; 52(6):953-68. DOI: 10.1016/j.neuron.2006.11.019. View

19.

Koyama Y . Endothelin ET Receptor-Mediated Astrocytic Activation: Pathological Roles in Brain Disorders. Int J Mol Sci. 2021; 22(9). PMC: 8122402. DOI: 10.3390/ijms22094333. View

20.

Allen N . Astrocyte regulation of synaptic behavior. Annu Rev Cell Dev Biol. 2014; 30:439-63. DOI: 10.1146/annurev-cellbio-100913-013053. View