Entrainment of prefrontal theta synchrony increases interbrain coupling and enhances social interaction in mouse models of autism

Social interaction requires the integration of information about self, other, and shared context. One of the proposed mechanisms supporting this coordination is interbrain synchrony – correlated neural activity between interacting individuals – yet its role in shaping social behavior remains unresolved. Here, we show that theta band synchrony in the medial prefrontal cortex (mPFC) is closely linked to social interaction in mice and often precedes its onset.

In male Shank2 mutant mice, a genetic model of social dysfunction, mPFC interbrain synchrony was diminished, along with a reduced population of mPFC neurons encoding multiple dimensions of social information. Optogenetic entrainment of theta synchrony was accompanied by increased interbrain coupling and social interaction in male Shank2-/- and Tbr1+/K228E mutant mice, two well-established genetic models of autism spectrum disorder (ASD). These findings identify prefrontal theta synchrony as a neural substrate that supports social behavior and provide a framework for understanding how coordinated neural activity across brains contributes to social interaction.

We would like to thank W. Hong (University of California, Los Angeles) for valuable discussions regarding the study. We would also like to acknowledge M.Jung (KAIST) for the critical reading of the manuscript.

We thank the veterinary team at Yonsei University College of Medicine for their support in animal care and maintenance. This research was supported by the National Research Foundation grant (RS-2024-31-0579) and the Ministry of Health and Welfare, Republic of Korea (RS-2024-00438988 and RS-2024-00405260) and the faculty research grant of Yonsei University College of Medicine (6-2022-0124). Department of Anatomy, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea Eunkyu Hwang, Soogeun Shin, Woohyun Kim, Hyung-Geun Yoon, Younghoon Kwon, Dongseok Seo & Eunee Lee Yonsei University College of Medicine, Seoul, Republic of Korea Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, Republic of Korea Department of Convergence IT Engineering, Pohang University of Science and Technology, Pohang, Republic of Korea Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon, Republic of Korea The authors declare no competing interests.

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