Astrocytic β-catenin signaling via TCF7L2 regulates synapse development and social behavior

Author:

Szewczyk Lukasz MateuszORCID,Lipiec Marcin AndrzejORCID,Liszewska Ewa,Meyza Ksenia,Urban-Ciecko Joanna,Kondrakiewicz Ludwika,Goncerzewicz Anna,Rafalko Kamil,Krawczyk Tomasz Grzegorz,Bogaj KarolinaORCID,Vainchtein Ilia DavidovichORCID,Nakao-Inoue HiromiORCID,Puscian Alicja,Knapska EwelinaORCID,Sanders Stephan J.ORCID,Jan Nowakowski Tomasz,Molofsky Anna VictoriaORCID,Wisniewska Marta BarbaraORCID

Abstract

AbstractThe Wnt/β-catenin pathway contains multiple high-confidence risk genes that are linked to neurodevelopmental disorders, including autism spectrum disorder. However, its ubiquitous roles across brain cell types and developmental stages have made it challenging to define its impact on neural circuit development and behavior. Here, we show that TCF7L2, which is a key transcriptional effector of the Wnt/β-catenin pathway, plays a cell-autonomous role in postnatal astrocyte maturation and impacts adult social behavior. TCF7L2 was the dominant Wnt effector that was expressed in both mouse and human astrocytes, with a peak during astrocyte maturation. The conditional knockout of Tcf7l2 in postnatal astrocytes led to an enlargement of astrocytes with defective tiling and gap junction coupling. These mice also exhibited an increase in the number of cortical excitatory and inhibitory synapses and a marked increase in social interaction by adulthood. These data reveal an astrocytic role for developmental Wnt/β-catenin signaling in restricting excitatory synapse numbers and regulating adult social behavior.

Publisher

Springer Science and Business Media LLC

Subject

Cellular and Molecular Neuroscience,Psychiatry and Mental health,Molecular Biology

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