Social regression stems from a latent phase of GABAergic dysfunction and sensory breakdown in a model of synaptopathy

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.