Estradiol-Mediated Spine Changes in the Dorsal Hippocampus and Medial Prefrontal Cortex of Ovariectomized Female Mice Depend on ERK and mTOR Activation in the Dorsal Hippocampus

Dendritic spine plasticity underlies the formation and maintenance of memories. Both natural fluctuations and systemic administration of 17 beta-estradiol (E-2) alter spine density in the dorsal hippocampus (DH) of rodents. DH E-2 infusion enhances hippocampal-dependent memory by rapidly activating extracellular signal-regulated kinase (ERK)-dependent signaling of mammalian target of rapamycin (mTOR), a key protein synthesis pathway involved in spine remodeling. Here, we investigated whether infusion of E-2 directly into the DH drives spine changes in the DH and other brain regions, and identified cell-signaling pathways that mediate these effects. E-2 significantly increased basal and apical spine density on CA1 pyramidal neurons 30 min and 2 h after infusion. DH E-2 infusion also significantly increased basal spine density on pyramidal neurons in the medial prefrontal cortex (mPFC) 2 h later, suggesting that E-2-mediated activity in the DH drives mPFC spinogenesis. The increase in CA1 and mPFC spine density observed 2 h after intracerebroventricular infusion of E-2 was blocked by DH infusion of an ERK or mTOR inhibitor. DH E-2 infusion did not affect spine density in the dentate gyrus or ventromedial hypothalamus, suggesting specific effects of E-2 on the DH and mPFC. Collectively, these data demonstrate that DH E-2 treatment elicits ERK- and mTOR-dependent spinogenesis on CA1 and mPFC pyramidal neurons, effects that may support the memory-enhancing effects of E-2.