Social regression stems from a latent phase of GABAergic dysfunction and sensory breakdown in a model of synaptopathy
5 affiliations
- 1Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi, 10, 16132 Genova, Italy
- 2Department of Experimental Medicine, Università degli Studi di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy
- 3IRCCS Azienda Ospedaliera Metropolitana, Largo Rosanna Benzi, 10, 16132 Genova, Italy
- 4The Open University Affiliated Research Centre at Istituto Italiano di Tecnologia, Genova, Italy
- 5Analytical Chemistry Facility, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy
Abstract
In autism spectrum disorder (ASD), children can exhibit a regressive phenotype with loss of previously acquired social and language skills in the first years of life. While the role of the GABAergic system in shaping neural circuits during development has been largely studied, its potential involvement in regressive phenotypes remains unclear. Here, we tracked the social and sensory development in Synapsin2 knockout (Syn2KO) mice, a model of ASD characterized by defective inhibitory tonic current, social deficits, and epilepsy in adulthood. We show that, after a transient early phase of impaired vocalization, young (PND 30) Syn2KO mice reached a normal social behavior. However, social behavior was regressively lost in adult (PND 120) mice, with the absence of vocalizations during the male-female interaction test associated with a drastic degeneration of the preoptic area-periaqueductal gray vocal GABAergic circuit. This deterioration began at earlier stages but was behaviorally latent. Adult Syn2KO mice also displayed sensory dysfunctions and dysregulation of the GABAergic system in the integrative posterior parietal cortex, with hyper-responsiveness of bimodal light- and sound-sensitive neurons that paralleled the social decline. Boosting tonic inhibition from birth with chronic treatment with the GABAA receptor agonist gaboxadol fully reversed social deficits, restored the integrity of vocal circuits, and the multimodal integration of sensory inputs. These results show that social regression in the Syn2KO model is a multiphase process characterized by early signs, a latent period of typical development, and a subsequent decline that can be reversed by enhancing tonic inhibition from development onward.
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BibTeX
@article{ciano2026social,
title = {{Social regression stems from a latent phase of GABAergic dysfunction and sensory breakdown in a model of synaptopathy}},
author = {Lorenzo Ciano and Sebastian Sulis Sato and Filippo Galluzzi and Arianna Benedetti and Sine Mandrup Bertozzi and Alessandro Esposito and Francesca Franchi and Dmytro Shmal and Chiara Penzo and Martino Caramia and Elisabetta Colombo and Anna Fassio and Andrea Armirotti and Fabio Benfenati and Caterina Michetti},
journal = {Molecular Psychiatry},
year = {2026},
month = jul,
doi = {10.1038/s41380-026-03751-9},
url = {https://doi.org/10.1038/s41380-026-03751-9},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Social regression stems from a latent phase of GABAergic dysfunction and sensory breakdown in a model of synaptopathy
AU - Lorenzo Ciano
AU - Sebastian Sulis Sato
AU - Filippo Galluzzi
AU - Arianna Benedetti
AU - Sine Mandrup Bertozzi
AU - Alessandro Esposito
AU - Francesca Franchi
AU - Dmytro Shmal
AU - Chiara Penzo
AU - Martino Caramia
AU - Elisabetta Colombo
AU - Anna Fassio
AU - Andrea Armirotti
AU - Fabio Benfenati
AU - Caterina Michetti
PY - 2026
DA - 2026/07/13
JO - Molecular Psychiatry
DO - 10.1038/s41380-026-03751-9
UR - https://doi.org/10.1038/s41380-026-03751-9
AB - In autism spectrum disorder (ASD), children can exhibit a regressive phenotype with loss of previously acquired social and language skills in the first years of life. While the role of the GABAergic system in shaping neural circuits during development has been largely studied, its potential involvement in regressive phenotypes remains unclear. Here, we tracked the social and sensory development in Synapsin2 knockout (Syn2KO) mice, a model of ASD characterized by defective inhibitory tonic current, social deficits, and epilepsy in adulthood. We show that, after a transient early phase of impaired vocalization, young (PND 30) Syn2KO mice reached a normal social behavior. However, social behavior was regressively lost in adult (PND 120) mice, with the absence of vocalizations during the male-female interaction test associated with a drastic degeneration of the preoptic area-periaqueductal gray vocal GABAergic circuit. This deterioration began at earlier stages but was behaviorally latent. Adult Syn2KO mice also displayed sensory dysfunctions and dysregulation of the GABAergic system in the integrative posterior parietal cortex, with hyper-responsiveness of bimodal light- and sound-sensitive neurons that paralleled the social decline. Boosting tonic inhibition from birth with chronic treatment with the GABAA receptor agonist gaboxadol fully reversed social deficits, restored the integrity of vocal circuits, and the multimodal integration of sensory inputs. These results show that social regression in the Syn2KO model is a multiphase process characterized by early signs, a latent period of typical development, and a subsequent decline that can be reversed by enhancing tonic inhibition from development onward.
SN - 1359-4184
SN - 1476-5578
ER -