Scientists Restore Shortened Neuronal Structures to Reverse Autism-like Behaviors in Mice

Using chemogenetic activation, researchers elongated the axon initial segment (AIS) of pyramidal neurons in the medial prefrontal cortex of a mouse model with a 15q11-13 duplication. A single injection of a designer drug restored AIS length and sodium-channel protein spacing, normalizing social interaction and reducing repetitive behavior.

Psypost

Duplication of chromosome region 15q11-13 is a known ASD risk factor. In the mice, this duplication caused a marked shortening of the AIS in a sub-layer of the medial prefrontal cortex, lowering neuronal excitability. The AIS, which initiates action potentials, can adapt its length in response to activity, suggesting a reversible substrate for circuit dysfunction.

Psypost

The study was led by Professor Masashi Fujitani (Shimane University) with collaborators from Kobe University and Hyogo Medical University. The team applied whole-cell patch-clamp recordings, retrograde tracing to map medial prefrontal-dorsal raphe projections, and chemogenetics—viral delivery of designer receptors activated by a synthetic ligand—to selectively stimulate this pathway.

Psypost

Across 214 mice, groups of 11 were tested behaviorally. Untreated ASD mice showed reduced social time in the three-chamber test and buried an average of 15 of 20 marbles in a 30-minute assay. One hour after chemogenetic activation, AIS length matched controls, social preference normalized, and marble-burial fell below two, indistinguishable from healthy mice.

Psypost

Fujitani described the AIS shortening as a reversible adaptation, indicating that targeted circuit modulation can restore function. He suggested AIS morphology could serve as a biomarker for abnormal circuits and argued that precise “switches” within pathways may be more effective than broad pharmacological treatments.

Psypost

The authors note that analyses used fixed tissue rather than live-cell imaging, overall excitability was measured without single-neuron recordings, and only one ASD mouse model was examined, limiting direct extrapolation to humans.

Psypost

• “One surprising finding was that the abnormalities we observed were not necessarily permanent,” Fujitani said.

Psypost

• “One important takeaway from our study is that changes in the axon initial segment (AIS) could potentially serve as a biomarker for detecting abnormal neural circuits in the brain,” Fujitani told PsyPost.

Psypost

• “One important limitation of our study is that it was conducted in mice, so further research is needed to determine whether the findings can be directly applied to humans,” Fujitani cautioned.

Psypost

• “In the long term, we hope to develop treatments that can target specific neural circuits in the human brain,” Fujitani added.

Psypost

The team proposes refining circuit-specific interventions with focused ultrasound and viral vectors to modulate AIS plasticity. Ongoing work will record single-cell activity and test additional ASD models, building a foundation for eventual clinical translation.

Psypost