Restoration of axon initial segment plasticity via chemogenetic activation rescues autism-related behaviors | Cell Death & Disease

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Restoration of axon initial segment plasticity via chemogenetic activation rescues autism-related behaviors

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Brain<br>Cellular neuroscience<br>Molecular neuroscience

Abstract<br>Autism spectrum disorder (ASD) presents a major clinical challenge, necessitating the identification of novel therapeutic targets rooted in its underlying pathophysiology. The axon initial segment (AIS) is the critical site for action potential initiation and a hub for homeostatic plasticity; however, its involvement in ASD remains poorly defined. Herein, we report significant structural and functional deficits in the AIS within a clinically relevant ASD mouse model harboring a 15q11-13 duplication (15q dup). We observed that pyramidal neurons in the medial prefrontal cortex (mPFC) exhibited shortened AIS, resulting in reduced neuronal excitability and impaired plasticity. Importantly, these abnormalities were specific to long-range circuits, including the mPFC–dorsal raphe nucleus (DRN) pathway, which is critical for social behavior. We employed a circuit-specific chemogenetic strategy that activates these mPFC–DRN projection neurons to test the reversibility of this phenotype. Remarkably, this targeted intervention normalized AIS structure and rescued core ASD-like behaviors, including social interaction deficits and repetitive behaviors. These results demonstrated that AIS alterations in this ASD model represent a reversible form of maladaptive plasticity, rather than permanent neuropathology. Our study highlights circuit-specific AIS modulation as a promising novel avenue for therapeutic interventions aimed at correcting fundamental neuronal excitability deficits in ASD.

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Acknowledgements<br>The authors thank Dr. Shigefumi Yokota and Dr. Kenichiro Kuwako for their valuable contributions and technical assistance. We also acknowledge the Interdisciplinary Center for Science Research and the Head Office for Research and Academic Information, Shimane University, Japan.

Funding<br>This work was supported by grants from the Japan Society for the Promotion of Science (JSPS) KAKENHI (23K07290 to MF and 22K07868 to YO), Shimane University Hospital Foundation for the Promotion of Advanced Medical Care to MF and the SU Capacity Building Project Toward a Sustainable Society (S-Spring) to XL and XZ.

Author information<br>Authors and Affiliations<br>Department of Anatomy and Neuroscience, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan<br>Yoshinori Otani, Xiaowei Zhu, Xinlang Liu & Masashi Fujitani

Department of Neurophysiology, Faculty of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan<br>Kohei Koga & Ryo Kawabata

Gladstone Institute of Neurological Disease, San Francisco, CA, USA<br>Hisao Miyajima

Department of Physiology and Cell Biology, Kobe University School of Medicine, Chuo-ku, Kobe, Hyogo, Japan<br>Toru Takumi

AuthorsYoshinori OtaniView author publications<br>Search author on:PubMed Google Scholar

Xiaowei ZhuView author publications<br>Search author on:PubMed Google Scholar

Xinlang LiuView author publications<br>Search author on:PubMed Google Scholar

Kohei KogaView author publications<br>Search author on:PubMed Google Scholar

Ryo KawabataView author publications<br>Search author on:PubMed Google Scholar

Hisao MiyajimaView author publications<br>Search author on:PubMed Google Scholar

Toru TakumiView author publications<br>Search author on:PubMed Google Scholar

Masashi FujitaniView author publications<br>Search author on:PubMed Google Scholar

Corresponding author<br>Correspondence to<br>Masashi Fujitani.

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Competing interests

The authors declare no competing interests.

Ethics statement

All animal protocols were approved by the Department of Experimental Animals, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University (approval numbers IZ4-4 and IZ7-12).

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work, the author(s) used Gemini and PaperPal to...