Multimodal synapse analysis reveals limitations in transplanted neuron integration mediated by TREM2

Neuron transplantation offers a promising approach for circuit restoration after injury, but depends crucially on adequate synaptic integration. Yet, our knowledge of the effects of the host injury environment on transplanted neuron (tN) network integration remains limited. Here, we used a stab wound injury model to examine how tN synapses mature and integrate using multimodal read-outs. Morphological, ultrastructural and functional electrophysiological analysis of tN synapses indicated that tN integration and functional maturation are partially stunted. Spatial transcriptomics revealed persistent inflammatory signatures at the transplant site including Trem2 upregulation. Strikingly, in an environment devoid of TREM2, synaptic integration as well as functional maturation of tNs, including action potential maturation and spontaneous firing, were almost fully rescued. Spatial transcriptomics further showed reduced inflammatory pathways and improved maturation of tNs in Trem2-/- brains. This study highlights the importance of tackling chronic inflammation for adequate tN integration.