Abstract

The adult cortex has a limited endogenous capacity for circuit repair or plasticity, such that stroke and traumatic brain injury can cause neuronal loss and permanently impair brain function. Remarkably, transplantation of embryonic interneurons from the medial ganglionic eminence (MGE) into the adult visual cortex (V1) can reopen a window of plasticity timed to the age of the donor cells, mimicking the endogenous critical period (CP). While this plasticity is robust and reproducible, the underlying molecular mechanisms remain unclear. Using single-nucleus transcriptomics, we proled both transplanted MGE interneurons and host V1 cells at three timepoints—before, during, and after the second CP. Our ndings suggest that MGE transplants reopen plasticity by (1) integrating into host circuits through progressive synapse formation, quantied with synaptic staining at early and late stages; (2) transiently modifying gene expression in host PV interneurons; and (3) engaging NRG1/ErbB4 signaling in a time- and cell-type-specic manner. To test whether this pathway is necessary, we transplanted NRG1 knockout interneurons. These cells migrated normally and exhibited healthy morphology, but failed to induce a second CP, as measured by intrinsic signal imaging. Additionally, we are currently performing monosynaptic rabies tracing to dene transplant connectivity. Together, our work reveals that successful circuit integration and precise molecular signaling—not survival alone—are essential for transplant-driven plasticity