SYNAPTIC REFINEMENT IN A MOUSE MODEL OF BEHAVIORAL REGRESSION AND EPILEPSY

Neurodevelopmental disorders, such as autism and epilepsy, can be defined as synaptopathies, as they arise from genetic and/or environmental factors that directly or indirectly impair synaptic function. These alterations lead to behavioral deficits that may emerge during early life or later in development. A loss of previously acquired skills, including social abilities, is referred to as behavioral regression, a phenomenon in which synaptic refinement is thought to play a critical role.
In this study, we aimed to characterize the pruning process in a model characterized by social regression and synaptic impairment, the Synapsin II knockout (Syn II KO) mouse. Synapsin II (Syn II) is a presynaptic phosphoprotein that regulates synaptic vesicle trafficking and neurotransmitter release, playing a key role in neuronal maturation. Here, we observed decreased dendritic spine density and a modest reduction in microglial density in cortical regions of Syn II KO mice, suggesting possible alterations in microglia-spine crosstalk.
To evaluate whether a potentiation of dendritic arborization during the critical period of development can rescue the regressive phenotype, we used a chemogenetic approach to boost spine plasticity. Specifically, we employed a genetically encoded engineered protein (GEEP) whose activity can be selectively modulated in living cells using rapamycin. Using adeno-associated viral vectors, GEEP was expressed in the brain of wild-type and Syn II KO mice during the critical period.
Chemogenetic activation of GEEP via rapamycin administration improved socio-behavioral deficits in adult Syn II KO mice. Future studies will clarify the relationships between social regression and spine pathology.