Multimodal synapse analysis reveals restricted integration of transplanted neurons remodeled by TREM2
Neural circuit responses arise from computations across diverse synapses within a neuron, making synaptic integration a crucial parameter to restore function after injury. Neuron transplantation offers a promising approach for circuit restoration after injury, but our knowledge of transplanted neuron (tN) synaptic connectivity remains limited. Here, we used a stab wound injury model, to examine how synapses of tNs mature and integrate using multimodal read-outs. We analyzed the morphological, ultrastructural and functional aspects of tN synapses and found surprising misalignments, such as many spines without synapses or many shaft synapses that are not inhibitory, pointing towards immature aspects even 3 months post transplantation. Spatial transcriptomics revealed persistent inflammatory signatures at the transplant site including Trem2 upregulation. Indeed, the excessive pruning of the brain-wide input connectome of tNs was much improved in an environment devoid of TREM2, highlighting the importance of tackling the chronic inflammation for adequate tN integration.