Top2a-dependent neuronal regulation of social behavior and persistent rescue of social deficit through PRC2-mediated epigenetic reprogramming.

Disruption of social behavior is a core feature of autism spectrum disorder (ASD), yet the molecular and cellular mechanisms governing social behavior development are not well understood. We previously identified topoisomerase IIα (Top2a) as a critical regulator of social behavior and restricted and repetitive behavior through antagonism of polycomb repressive complex 2 (PRC2)-mediated H3K27 trimethylation (H3K27me3), based mainly on pharmacological perturbations during embryogenesis in zebrafish and mouse. However, whether neuronal Top2a is genetically required for social behavior in mammals, and whether PRC2 inhibition can rescue genetically induced social deficits, remain untested. Here, we establish a neuron-specific Top2a conditional knockout mouse model and demonstrate that neuronal Top2a haploinsufficiency selectively impairs social interaction without inducing restricted and repetitive behaviors or cognitive deficits. Pharmacological inhibition of PRC2 using the EZH2 inhibitor tazemetostat, combined with elacridar to facilitated blood-brain barrier penetration, robustly rescues social deficits in Top2a conditional knockout mice. Strikingly, a one-week oral dosing regimen produced a rescue effect that persisted for up to two months after treatment cessation, far exceeding the temporal window typically observed for neuromodulatory drugs targeting neurotransmitter systems. These results showcase the unique capability of epigenetic modulatory therapy to induce durable behavioral improvements and their therapeutic potential for treating social dysfunction in neuropsychiatric disorders. Together, our results provide direct genetic evidence that neuronal Top2a governs social behavior in mice and establish the neuronal Top2a-PRC2 axis as a conserved, targetable epigenetic pathway regulating social behavior.