Vangl2 participates in the correct temporal connectivity of the DG-CA3 circuits and in declarative memory processes

Vangl2, a central protein of the Wnt/PCP pathway, is a known key player in morphogenesis. One of our recent studies also linked it to the regulation of cognitive function. However, we lack information on the precise role of Vangl2 in different types of synapses associated with specific cognitive processes. Here, we found that Vangl2 is essential for the development and function of a specific hippocampal connection, the MFB/TE synapse. We show that Vangl2 is enriched in the postnatal hippocampus, specifically in the DG and CA3. Using 3D reconstruction of confocal and SBFSEM acquisitions, we show that early genetic ablation of vangl2 in mice leads to aberrant morphogenesis of the MFB synapse with long-lasting consequences on its structural plasticity. This morphological defect is accompanied by molecular changes in the pre- and post-synaptic compartments, as well as deficits in basal transmission. Finally, we show that early loss of Vangl2 leads to specific deficits in baseline memory in adult animals. Overall, we show that Vangl2-dependent mechanisms are essential for the correct postnatal morphogenesis and function of the MFB/TE synapse, and that alteration of these mechanisms has long-lasting consequences on memory flexibility. Our data reveal the importance of the PCP pathway in establishing hippocampal synaptic connections and in long-term memory.