Thrombospondin-1 regulates synaptic transmission in hippocampal field CA2 and social behavior in mice

Thrombospondin 1 (TSP1) is a secreted extracellular matrix glycoprotein, which mediates cell-to-cell and cell-to-matrix interactions. In humans, mutations in THBS1, which encodes TSP1, are associated with neurodevelopmental disorders, but the underlying neurobiological mechanisms are unclear. TSP1 is secreted by astrocytes, and has been shown to promote synaptogenesis in vitro, but knowledge about its function in vivo is limited. In this study, we assessed TSP1's modulation of synaptic function and cognitive and emotional processes using TSP1 knockout mice. Deletion of TSP1 led to decreased perineuronal net density and strengthened synaptic transmission in hippocampal field CA2, but not CA1. Accordingly, TSP1 KO mice showed severely disrupted social interaction, as well as emotional alterations, but normal spatial memory. Collectively, our findings identify TSP1 as a crucial modulator of synaptic function in CA2 and social and emotional processes. Furthermore, our work delineates a mechanism linking altered TSP1 signaling with psychiatric conditions with altered social and emotional function.