Abstract
SummaryIn the hippocampus, dentate gyrus granule cells connect to CA3 pyramidal cells via their axons, the mossy fibers (Mf). The synaptic terminals of Mfs (Mf boutons, MfBs) form large and complex synapses with thorny excrescences (TE) on the proximal dendrites CA3 pyramidal cells (PCs). MfB/TE synapses have distinctive “detonator” properties due to low intitial release probability and large presynaptic facilitation. The molecular mechanisms shaping the morpho-functional properties of MfB/TE synapses are still poorly understood, though alterations in their morphology are associated with Down syndrome, intellectual disabilities, and Alzheimer’s disease. Here, we identify the core PCP geneVangl2as essential to the morphogenesis and function of MfB/TE synapses. Vangl2 colocalises with the presynaptic heparan sulfate proteoglycan glypican 4 (GPC4) to stabilise the postsynaptic orphan receptor GPR158. Embryonic loss of Vangl2 disrupts the morphology of MfBs and TEs, impairs ultrastructural and molecular organisation, resulting in defective synaptic transmission and plasticity. In adult, the early loss of Vangl2 results in a number of hippocampus-dependent memory deficits including characteristic flexibility of declarative memory, organisation and retention of working/ everyday-like memory. These deficits also lead to abnormal generalisation of memories to salient cues and diminished ability to form detailed contextual memories. Together, these results establish Vangl2 as a key regulator of DG-CA3 connectivity and functions.HighlightsVangl2 is a key regulator of MfB/TE synapses morphogenesis and plasticity in CA3Vangl2-mediated GPC4-GPR158 interaction maintains MfB-TE pre-synaptic morphology and functionVangl2deletion affects declarative memory in adult miceVangl2 function is necessary for contextual learning and its loss leads toa maladaptive fear memory for salient cues
Publisher
Cold Spring Harbor Laboratory