Histone H2A.Z is required for androgen receptor-mediated effects on fear memory.

Epigenetic factors translate environmental signals into stable outcomes, but how they are influenced by regulators of plasticity remain unclear. We previously showed that androgen receptor overexpression inhibited fear memory in male mice and increased expression of the histone variant H2A.Z, a novel epigenetic regulator of memory. Here, we used conditional-inducible H2A.Z knockout mice to investigate how H2A.Z deletion influences androgenic regulation of fear memory. We showed that conditional inducible H2A.Z deletion blocked memory-enhancing effects of androgen depletion (induced by gonadectomy), and of pharmacological inhibition of the androgen receptor with flutamide. Similarly, H2A.Z deletion blocked the memory-reducing effects of DHT, and DHT treatment in cultured hippocampal neurons altered H2A.Z binding, suggesting that AR is an H2A.Z regulator in neurons. Overall, these data show that fear memory formation is regulated by interactions between sex hormones and epigenetic factors, which has implications for sex differences in fear-related disorders.