Effects of Inhibiting Proteasome Activity on the Memory-Enhancing Effects of 17��-Estradiol in Ovariectomized Female Mice
Mentor 1
Karyn Frick
Start Date
28-4-2023 12:00 AM
Description
Although 17��-estradiol (E2) is well known to enhance hippocampus-dependent memory in mice, the means through which it does so remain unclear. A potential underlying mechanism is through regulating protein degradation mediated by the ubiquitin-proteasome system (UPS). The UPS functions by tagging proteins with several ubiquitin molecules that serve as a signal for degradation by the 26S proteasome complex. The purpose of this study was to determine whether E2 requires 26S proteasome activity to enhance spatial and object recognition memory formation in ovariectomized (OVX) female mice. To test this, a dose of proteasome inhibitor ��-lactone (��-lac) that did not impair spatial and object recognition memory on its own in OVX mice had to be identified. Object placement (OP) and object recognition (OR) tasks were used to assess spatial and object recognition memory, respectively. Both tasks consisted of a training phase, during which mice were given two identical objects and were allowed 20 minutes to accumulate 30 seconds of exploration between the two. During testing, one of the objects was either moved (OP) or replaced with a novel object (OR), and mice were given the same time to explore the two. Memory enhancement was defined as animals spending greater time than chance (>15 sec) with the moved or novel object. Results from the dose-response study indicate that post-training infusion of 32 or 16 ng/µl ��-lac impaired OP and OR memory on its own. In a separate cohort of mice, 8 ng/µl of ��-lac was infused in combination with E2. Preliminary results from this experiment showed that mice that received 8 ng/µl in addition to E2 spent an amount of time roughly equal to chance with the moved or novel object, indicating that UPS activity is critical for the memory enhancing effects of E2 in OVX female mice.
Effects of Inhibiting Proteasome Activity on the Memory-Enhancing Effects of 17��-Estradiol in Ovariectomized Female Mice
Although 17��-estradiol (E2) is well known to enhance hippocampus-dependent memory in mice, the means through which it does so remain unclear. A potential underlying mechanism is through regulating protein degradation mediated by the ubiquitin-proteasome system (UPS). The UPS functions by tagging proteins with several ubiquitin molecules that serve as a signal for degradation by the 26S proteasome complex. The purpose of this study was to determine whether E2 requires 26S proteasome activity to enhance spatial and object recognition memory formation in ovariectomized (OVX) female mice. To test this, a dose of proteasome inhibitor ��-lactone (��-lac) that did not impair spatial and object recognition memory on its own in OVX mice had to be identified. Object placement (OP) and object recognition (OR) tasks were used to assess spatial and object recognition memory, respectively. Both tasks consisted of a training phase, during which mice were given two identical objects and were allowed 20 minutes to accumulate 30 seconds of exploration between the two. During testing, one of the objects was either moved (OP) or replaced with a novel object (OR), and mice were given the same time to explore the two. Memory enhancement was defined as animals spending greater time than chance (>15 sec) with the moved or novel object. Results from the dose-response study indicate that post-training infusion of 32 or 16 ng/µl ��-lac impaired OP and OR memory on its own. In a separate cohort of mice, 8 ng/µl of ��-lac was infused in combination with E2. Preliminary results from this experiment showed that mice that received 8 ng/µl in addition to E2 spent an amount of time roughly equal to chance with the moved or novel object, indicating that UPS activity is critical for the memory enhancing effects of E2 in OVX female mice.
