Behavioral regression in Syn II KO mice: from latent synaptopathy to overt dysfunctions in multisensory social processing

Regression, understood as the loss of previously acquired behaviors, affects 20-30% of patients with Autism Spectrum Disorder (ASD). Children exhibit this loss of functional behaviors within the first years of life. Nowadays, the mechanism behind this regressive process is still unknown. To improve our knowledge about ASD regression and find selected target treatments, it is important to establish a model with regressive features. In the present project, we showed that the Synapsin II Knockout (SynII KO) mouse loses previously acquired social and cognitive abilities in adulthood, and propose it as a valid model for the study of regression. Synapsin II is a presynaptic phosphoprotein belonging to the Synapsin family (Syns) involved in neuronal development and in the modulation of neurotransmitter release at presynaptic terminals. Mutations in the SYN2 gene are associated to ASD and epilepsy, and in line, mice lacking this gene exhibit an ASD-like behavior and develop generalized seizures starting from two-three months of age. Here, we reported that 1-month-old SynII KO mice showed no defects in social and cognitive behaviors, which instead are manifested in adult and epileptic mice, in association with a disrupted sensory and multisensory integration. We showed that the regressive manifestations were not related to epilepsy and that synaptic alterations appeared with a different timing in the diverse brain regions. Our data suggest the existence of an ASD-genesis latent period during which plasticity mechanisms contrast the precocious excitatory/inhibitory (E/I) imbalance and thus mask the behavioral deficits. These corrective mechanisms seem to disappear in adults when the period of maximum plasticity is closed, resulting in the appearance of overt behavioral symptoms. Preliminary pharmacological studies suggested that an early rebalance of E/I systems can drive a correct maturation of synaptic contacts and restore the early altered behavioral signs. Overall, this study proposes the SynII KO mouse as an ideal candidate for the study of ASD with regressive pattern.