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

doi:10.1016/j.cell.2021.06.018

GABA-receptive microglia selectively sculpt developing inhibitory circuits

Cell. 2021 Jul 22;184(15):4048-4063.e32. doi: 10.1016/j.cell.2021.06.018. Epub 2021 Jul 6.

Authors

Emilia Favuzzi¹, Shuhan Huang¹, Giuseppe A Saldi², Loïc Binan³, Leena A Ibrahim¹, Marian Fernández-Otero¹, Yuqing Cao¹, Ayman Zeine⁴, Adwoa Sefah¹, Karen Zheng⁵, Qing Xu⁶, Elizaveta Khlestova⁴, Samouil L Farhi³, Richard Bonneau⁷, Sandeep Robert Datta⁴, Beth Stevens⁸, Gord Fishell⁹

Affiliations

¹ Department of Neurobiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
² Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Biology, New York University, New York, NY 10003, USA.
³ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁴ Department of Neurobiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
⁵ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁶ New York University Abu Dhabi, Abu Dhabi, UAE.
⁷ Department of Biology, New York University, New York, NY 10003, USA; Center for Computational Biology, Flatiron Institute, New York, NY 10010, USA; Center for Data Science, New York University, New York, NY 10011, USA.
⁸ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, MA 02115, USA.
⁹ Department of Neurobiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: [email protected].

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 GABA_B 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.

Keywords: cerebral cortex; development; glia-neuron interactions; inhibitory synapses; interneurons; microglia; neurodevelopmental disorders.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Behavior, Animal
Gene Expression Regulation
HEK293 Cells
Humans
Mice
Microglia / metabolism*
Neural Inhibition / physiology*
Parvalbumins / metabolism
Phenotype
Receptors, GABA-B / metabolism
Synapses / physiology
Transcription, Genetic
gamma-Aminobutyric Acid / metabolism*

Substances

Parvalbumins
Receptors, GABA-B
gamma-Aminobutyric Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding