Abstract Regulatory mechanisms associated with repeat-rich sequences and chromosomal conformations in mature neurons remain unexplored. Here, we map cell-type specific chromatin domain organization in adult mouse cerebral cortex and report strong enrichment of Endogenous Retrovirus 2 (ERV2) repeat sequences in the neuron-specific heterochromatic B 2 NeuN+ megabase-scaling subcompartment. Single molecule long-read sequencing and comparative Hi-C chromosomal contact mapping in wild-derived SPRET/EiJ ( Mus spretus ) and laboratory inbred C57BL/6J ( Mus musculus ) reveal neuronal reconfigurations tracking recent ERV2 expansions in the murine germline, with significantly higher B 2 NeuN+ contact frequencies at sites with ongoing insertions in Mus musculus . Neuronal ablation of the retrotransposon silencer Kmt1e/Setdb1 triggers B 2 NeuN+ disintegration and rewiring with open chromatin domains enriched for cellular stress response genes, along with severe neuroinflammation and proviral assembly with infiltration of dendrites . We conclude that neuronal megabase-scale chromosomal architectures include an evolutionarily adaptive heterochromatic organization which, upon perturbation, results in transcriptional dysregulation and unleashes ERV2 proviruses with strong neuronal tropism.