Autism spectrum disorder (ASD) is an innate brain developmental disorder that often manifests from early childhood. While genetic factors and differences in brain development are known to be involved, a definitive cure has yet to be established. Understanding and potentially reversing the underlying neurological abnormalities is a major challenge in neuroscience.
This feat has now been made possible by a collaborative research group led by Prof. Masashi Fujitani and Assistant Prof. Yoshinori Otani from the Department of Anatomy and Neuroscience, Faculty of Medicine, Shimane University, Japan, along with Prof. Toru Takumi from Kobe University and Associate Prof. Kohei Koga from Hyogo Medical University. In a study published in the renowned journal Cell Death & Disease on May 19, 2026, the team analyzed an ASD mouse model (15q dup mice) carrying genetic duplications associated with human ASD. The researchers discovered prominent abnormalities in the "axon initial segment" (AIS)—a critical region at the root of a neuron where electrical signals (action potentials) are generated. Specifically, in the neural circuit projecting from the prefrontal cortex (a region vital for social behavior) to the dorsal raphe nucleus, the AIS was abnormally shortened, resulting in reduced neuronal excitability (firing capacity).
"Given that we observed significant structural abnormalities in the axon initial segment of the ASD mouse model, we sought to understand if these changes were reversible," explains Prof. Fujitani. "To investigate this, we utilized a chemogenetic technique known as DREADD, which enabled us to artificially and selectively activate the specific neural circuit projecting from the prefrontal cortex to the dorsal raphe nucleus."
The results of this study showed that targeted chemogenetic activation successfully recovered the shortened length of the axon initial segment to its normal level. Accompanying this structural restoration was a marked improvement in the mice's ASD-like behavioral abnormalities, including a recovery in sociability and a reduction in repetitive behaviors.
To Prof. Fujitani and the research group, these results signify a major milestone. "Our study demonstrates that the structural brain abnormalities and impaired AIS plasticity observed in ASD animal models are not irreversible damage, but rather a reversible and recoverable phenomenon," comments Prof. Fujitani. "The evidence that behavioral abnormalities can be rescued by intervening in specific neural circuits provides a solid foundation for entirely new therapeutic strategies for autism spectrum disorder in the future."
