Ovarian hormone loss impairs excitatory synaptic transmission at hippocampal CA3-CA1 synapses

Premature and long-term ovarian hormone loss following ovariectomy (OVX) is associated with cognitive impairment. This condition is prevented by estradiol (E₂) therapy when initiated shortly following OVX but not after substantial delay. To determine whether these clinical findings are correlated with changes in synaptic functions, we used adult OVX rats to evaluate the consequences of short-term (7-10 d, OVX_Control) and long-term (~5 months, OVX_LT) ovarian hormone loss, as well as subsequent in vivo E₂ treatment, on excitatory synaptic transmission at the hippocampal CA3-CA1 synapses important for learning and memory. The results show that ovarian hormone loss was associated with a marked decrease in synaptic strength. E₂ treatment increased synaptic strength in OVX_Control but not OVXLT rats, demonstrating a change in the efficacy for E₂ 5 months following OVX. E2 also had a more rapid effect: within minutes of bath application, E₂ acutely increased synaptic strength in all groups except OVX_LT rats that did not receive in vivo E₂ treatment. E₂'s acute effect was mediated postsynaptically, and required Ca²⁺ influx through the voltage-gated Ca²⁺ channels. Despite E₂'s acute effect, synaptic strength of OVX_LT rats remained significantly lower than that of OVX_Control rats. Thus, changes in CA3-CA1 synaptic transmission associated with ovarian hormone loss cannot be fully reversed with delayed E₂ treatment. Given that synaptic strength at CA3-CA1 synapses is related to the ability to learn hippocampus-dependent tasks, these findings provide additional insights for understanding cognitive impairment-associated long-term ovarian hormone loss and ineffectiveness for delayed E₂ treatment to maintain cognitive functions.