GABA-receptive microglia selectively sculpt developing inhibitory circuits

Emilia Favuzzi, Shuhan Huang, Giuseppe A. Saldi, Loïc Binan, Leena A. Ibrahim, Marian Fernández-Otero, Yuqing Cao, Ayman Zeine, Adwoa Sefah, Karen Zheng, Qing Xu, Elizaveta Khlestova, Samouil L. Farhi, Richard Bonneau, Sandeep Robert Datta, Beth Stevens, Gord Fishell*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

122 Scopus citations

Abstract

Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and brain wiring. However, whether the remodeling of distinct synapse types during development is mediated by specialized microglia is unknown. Here, we show that GABA-receptive microglia selectively interact with inhibitory cortical synapses during a critical window of mouse postnatal development. GABA initiates a transcriptional synapse remodeling program within these specialized microglia, which in turn sculpt inhibitory connectivity without impacting excitatory synapses. Ablation of GABAB receptors within microglia impairs this process and leads to behavioral abnormalities. These findings demonstrate that brain wiring relies on the selective communication between matched neuronal and glial cell types.

Original languageEnglish (US)
Pages (from-to)4048-4063.e32
JournalCell
Volume184
Issue number15
DOIs
StatePublished - Jul 22 2021

Bibliographical note

Funding Information:
We thank Plexxikon for PLX5622, B. Bettler for Gabbr1-floxed allele, and G. Feng for Tmem119 CreER and Tmem119 GFP alleles. We thank L. Dissing-Olesen for advice on microglia isolation and suggestions on the project. We thank V. Regulapati for help with IHC, J. Dimidschstein for sharing the S5E2 plasmid, and L. Guo for help with AAV production. We are grateful to members of the Fishell laboratory for stimulating discussions. We thank B. Dejanovic, E. Lebois, and J. Dimidschstein for feedback on the manuscript. E.F. was supported by EMBO ( ALTF 444-2018 ) and FY21 Hearst Fellowships . Work in the G.F. laboratory is supported by the NIH ( R01 NS081297 , R01 MH071679 , UG3 MH120096 , and P01 NS074972 ), the Simons Foundation SFARI ( 566615 ), and the Harvard’s Dean Initiative . MERFISH work was supported by RF1 MH121289 from NIMH and a Joint Broad-Israel Science Foundation Research Grant. The HMS Neuro Imaging facility is funded by NINDS P30 Core Center ( NS072030 ).

Funding Information:
We thank Plexxikon for PLX5622, B. Bettler for Gabbr1-floxed allele, and G. Feng for Tmem119CreER and Tmem119GFP alleles. We thank L. Dissing-Olesen for advice on microglia isolation and suggestions on the project. We thank V. Regulapati for help with IHC, J. Dimidschstein for sharing the S5E2 plasmid, and L. Guo for help with AAV production. We are grateful to members of the Fishell laboratory for stimulating discussions. We thank B. Dejanovic, E. Lebois, and J. Dimidschstein for feedback on the manuscript. E.F. was supported by EMBO (ALTF 444-2018) and FY21 Hearst Fellowships. Work in the G.F. laboratory is supported by the NIH (R01 NS081297, R01 MH071679, UG3 MH120096, and P01 NS074972), the Simons Foundation SFARI (566615), and the Harvard's Dean Initiative. MERFISH work was supported by RF1MH121289 from NIMH and a Joint Broad-Israel Science Foundation Research Grant. The HMS Neuro Imaging facility is funded by NINDS P30 Core Center (NS072030). Conceptualization, E.F.; Methodology, E.F. L.B. Q.X. and S.F.; Software, E.F. G.A.S. L.B. A.Z. and K.Z.; Formal Analysis, E.F. S.H. G.A.S. L.B. L.A.I. A.Z. A.S. and E.K.; Investigation, E.F. S.H. L.B. L.A.I. Y.C. and M.F.-O.; Resources, S.F. S.R.D. B.S. and G.F.; Data Curation, E.F. and G.A.S.; Writing ? Original Draft, E.F. and G.F.; Writing ? Review & Editing, all co-authors; Visualization, E.F. and G.A.S.; Supervision, R.B. S.R.D. B.S. and G.F.; Project Administration, E.F.; Funding Acquisition, E.F. and G.F. B.S. serves on the SAB and is a minor shareholder of Annexon. G.F. is a founder of Regel. The other authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list.

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

  • cerebral cortex
  • development
  • glia-neuron interactions
  • inhibitory synapses
  • interneurons
  • microglia
  • neurodevelopmental disorders

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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