Chemico-genetic discovery of astrocytic control of inhibition in vivo

• Published in: Nature (London) Vol. 588; no. 7837; pp. 296 - 302
• Main Authors: Takano, Tetsuya, Wallace, John T., Baldwin, Katherine T., Purkey, Alicia M., Uezu, Akiyoshi, Courtland, Jamie L., Soderblom, Erik J., Shimogori, Tomomi, Maness, Patricia F., Eroglu, Cagla, Soderling, Scott H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.12.2020; Nature Publishing Group
• Subjects: 13; 13/106; 14; 14/19; 631/378/2571/2577; 631/378/2596/1308; 631/378/87; 82; 82/58; Analysis; Animals; Astrocytes; Astrocytes - chemistry; Astrocytes - cytology; Astrocytes - metabolism; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Cell Adhesion Molecules, Neuronal - metabolism; Cell Shape; Cell surface; Central nervous system; Chemical properties; Complementation; Control; CRISPR; Depletion; Female; GABAergic Neurons - cytology; GABAergic Neurons - metabolism; gamma-Aminobutyric Acid - metabolism; Genetic aspects; Genetic Complementation Test; Gephyrin; Glutamatergic transmission; HEK293 Cells; Humanities and Social Sciences; Humans; Inhibition (Neurophysiology); Male; Mice; Molecular modelling; Morphogenesis; multidisciplinary; Nervous system; Neural Inhibition; Neurons; Neurons - cytology; Neurons - metabolism; Neuropil; Proteins; Proteome - metabolism; Proteomes; Proteomics; Science; Science (multidisciplinary); Synapses; Synapses - chemistry; Synapses - metabolism; Synaptic density; Synaptogenesis; γ-Aminobutyric acid; United States
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-020-2926-0

Perisynaptic astrocytic processes are an integral part of central nervous system synapses 1 , 2 ; however, the molecular mechanisms that govern astrocyte–synapse adhesions and how astrocyte contacts control synapse formation and function are largely unknown. Here we use an in vivo chemico-genetic approach that applies a cell-surface fragment complementation strategy, Split-TurboID, and identify a proteome that is enriched at astrocyte–neuron junctions in vivo, which includes neuronal cell adhesion molecule (NRCAM). We find that NRCAM is expressed in cortical astrocytes, localizes to perisynaptic contacts and is required to restrict neuropil infiltration by astrocytic processes. Furthermore, we show that astrocytic NRCAM interacts transcellularly with neuronal NRCAM coupled to gephyrin at inhibitory postsynapses. Depletion of astrocytic NRCAM reduces numbers of inhibitory synapses without altering glutamatergic synaptic density. Moreover, loss of astrocytic NRCAM markedly decreases inhibitory synaptic function, with minor effects on excitation. Thus, our results present a proteomic framework for how astrocytes interface with neurons and reveal how astrocytes control GABAergic synapse formation and function. A cell-surface fragment complementation strategy is used to identify the proteome at the junction of astrocytes and synapses in vivo, and shows that NRCAM expressed in astrocytes has a key role in regulating inhibitory synapse function.