Chronic Aromatase Inhibition Attenuates Synaptic Plasticity in Ovariectomized Mice

Brain-derived estrogen (17β-estradiol, E2) is a neuromodulator that plays important roles in neural plasticity and network excitability. Chronic inhibition of estrogen synthesis is used in adjuvant breast cancer therapy for estrogen receptor-positive tumors and may have been associated with cognitive and affective side effects. Here, we have developed a model of adjuvant therapy in female ovariectomized mice in which the E2 biosynthetic enzyme aromatase is inhibited by letrozole (1 mg/kg/day, i.p., for up to 3 weeks), Using two-photon longitudinal in vivo imaging in Thy1-GFP-M mice, we found that spine density in the apical dendrites of neocortical layer 5 pyramidal cells was unaffected by letrozole treatment but spine turnover was reduced. LTP in layer 4 to layer 2/3 synapses in the somatosensory cortex was also reduced in slices from letrozole-treated mice, showing deficits in structural and functional plasticity resulting from aromatase inhibition. Ovariectomized mice performed worse than intact control mice in the novel object recognition test but, surprisingly, letrozole treatment rescued this deficit.