Ovarian Hormone Loss Impairs Excitatory Synaptic Transmission at Hippocampal CA3–CA1 Synapses

Abstract

Premature and long-term ovarian hormone loss following ovariectomy (OVX) is associated with cognitive impairment. This condition is prevented by estradiol (E 2 ) 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 (ϳ5 months, OVX LT ) ovarian hormone loss, as well as subsequent in vivo E 2 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. E 2 treatment increased synaptic strength in OVX Control but not OVX LT rats, demonstrating a change in the efficacy for E 2 5 months following OVX. E 2 also had a more rapid effect: within minutes of bath application, E 2 acutely increased synaptic strength in all groups except OVX LT rats that did not receive in vivo E 2 treatment. E 2 's acute effect was mediated postsynaptically, and required Ca 2ϩ influx through the voltage-gated Ca 2ϩ channels. Despite E 2 '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 E 2 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 E 2 treatment to maintain cognitive functions.

Estradiol replacement extends the window of opportunity for hippocampal function

“…In aged OVX rats, the duration of ovarian hormone deprivation dictates whether E2 replacement will be beneficial for hippocampal spine density, synaptic physiology, and learning, supporting the critical window hypothesis (Bohacek and Daniel, 2010, Daniel, et al, 2006a, Gibbs, 2000, Gibbs, et al, 2009, Savonenko and Markowska, 2003, Smith, et al, 2010, Wu, et al, 2013). We previously reported that up to 15 months post-OVX, E2 replacement is capable of increasing CA1 dendritic spine density, GluN2B-mediated transmission, NMDAR/AMPAR ratio, and LTP similar to that in young adult OVX rats following a 2 week deprivation (Smith and McMahon, 2005, Smith and McMahon, 2006, Smith, et al, 2010).…”

High-fat diet impairs spatial memory and hippocampal intrinsic excitability and sex-dependently alters circulating insulin and hippocampal insulin sensitivity

“…Much of the published physiological research with female rats involves ovariectomized subjects. Ovarian hormone loss results in rapid progressive loss of CA3–CA1 synaptic transmission [ 66 ], so estradiol administration is a common corrective. Unfortunately, despite noncyclic estradiol treatment, many studies report timing-, concentration-, and/or subject-dependent effects [ 67 ], i.e., increased variability in females that does not improve experimental clarity.…”

Infection‐induced endothelial amyloids impair memory

“…Hippocampal slices were visualized using a fixed-stage upright microscope (Leica Biosystems) equipped with infrared differential interference contrast optics. The recording chamber was continuously superfused with ACSF containing SR95531 (2 mM) and CGP55845 (1 mM) to block inhibitory synaptic transmission and flowing at 1-2 ml/min as we previously described (31)(32)(33). Both recording and stimulating electrodes were pulled from filamented borosilicate pipettes (BF150-86-10; Sutter Instrument, Novato, CA, USA) and filled with ACSF with tip resistance of 1 and 0.7 MV, respectively.…”