The causal link among higher-order chromatin loops, CTCF occupancy, and mRNA levels in post-mitotic human neurons remains an open question. Here, we summarize the field of epigenetics and chromatin in neuroscience, examine neural model systems, and build an auxin-inducible degron to deplete the architectural protein CTCF and disrupt loops genome-wide on short time scales during human induced pluripotent stem cell (iPSC)-derived post-mitotic neuronal maturation. We find thousands of ablated and hundreds of ectopically formed loops upon auxin treatment in post-mitotic neurons. By contrast to previous reports in dividing cell lines, disruption of CTCF-mediated enhancer-promoter and promoter-promoter loops significantly reduces mRNA levels of critical synaptic plasticity and neural cell adhesion genes. Upon pharmacological stimulation, CTCF depleted neurons exhibit defective activity-dependent gene expression. Our data uncover CTCF-mediated loops as an epigenetic shield against dysregulation of synaptic gene expression during the maturation of human neurons.