How fluctuations in ovarian hormones contribute to the development of major depressive disorder (MDD), and how they impact antidepressant efficacy continues to be understudied and ill-defined, despite women being diagnosed with MDD twice as often as men. This is unacceptable given that women make up half of the world's population and all undergo loss of ovarian hormones in menopause, increasing risk of depression and cognitive deficits. Memory impairment, the most commonly reported cognitive symptom associated with MDD, is linked with decreased hippocampal volume and neurogenesis, implicating hippocampal dysfunction. Importantly, 17? estradiol (E2), the major ovarian hormone which has both antidepressant and cognitive-enhancing effects, directly opposes the negative consequences of stress and glucocorticoids by increasing neurogenesis, dendritic spine density, synaptic plasticity, and learning and memory. Therefore, significant fluctuations in E2 increase vulnerability of hippocampal circuits to stress, potentially contributig to the greater incidence of MDD in women. Unfortunately, currently available treatments strictly target improving mood, with much less focus on therapeutic development to reverse the associated cognitive dysfunction. Thus, identifying therapeutic strategies and cellular mechanisms that target both mood and cognitive deficits are key to improving treatment of depression in women. Using surgically menopausal rats, we previously reported that E2 replacement increases hippocampal synaptic function and learning, and decreases acquisition of depression-like behavior following inescapable shock, confirming its beneficial effects on cognition and resilience to stress. Remarkably, a striking overlap exists between the plasticity related molecules required for the E2-induced increase in memory with those required for the rapid antidepressant effects of acute ketamine. Even more striking is that the E2-induced increase in GluN2B current, which is required for increasing LTP and novel object recognition, also occurs following acute ketamine treatment, suggesting that ketamine may transiently improve cognitive function. Thus, these shared mechanisms indicate critical interactions exist between ovarian hormones and ketamine in improving depression symptoms. Here, using behavior and brain slice electrophysiology we will investigate shared mechanisms between E2 and ketamine, with a focus on excitatory circuits and GABAergic interneurons in hippocampus and mechanisms that contribute to learning and memory. Clearly, this is an area of research that is urgently needed to improve treatment efficacy in women. Importantly, results obtained herein will define the mechanisms driving the antidepressant and cognitive effects of E2 and ketamine that are critical to advancing their effective therapeutic use either alone or together in treating depression and associated cognitive deficits in women over the lifespan.

Public Health Relevance

How fluctuations in ovarian hormones contribute to the development of major depressive disorder(MDD) and impact antidepressant efficacy continues to be ill-defined, despite women being diagnosed with MDD twice that of men. Currently, acute ketamine use for treatment-resistant depression is increasing due to its rapid beneficial effects but information is incomplete regarding potential gender differences in ketamine efficacy. This proposal will investigate the mechanistic interactions between E2 and ketamine on depression-like behavior, hippocampal synaptic function, and cognition in surgically menopausal rats.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZRG1)
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Winsky, Lois M
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University of Alabama Birmingham
Anatomy/Cell Biology
Schools of Medicine
United States
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Widman, Allie J; McMahon, Lori L (2018) Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy. Proc Natl Acad Sci U S A 115:E3007-E3016