PROJECT SUMMARY
Patients with Alzheimer Disease (AD) are at increased risk of seizures. Women show higher rates of AD than
men, and loss of neuroprotective effects of ovarian hormones, such as estradiol, during and after menopause is
considered to be a factor in cognitive and memory deficits of AD. However, estradiol is primarily linked to seizure-
promoting effects in epilepsy. Estradiol thus may have both beneficial effects supporting cognitive function and
detrimental (proconvulsant) effects in AD with comorbid seizures. Estradiol is synthesized from testosterone by
the aromatase enzyme. Brain areas that are highly implicated in both AD and epilepsy, such as hippocampus
and cortex, express high levels of aromatase in both males and females. Previous studies indicate that
aromatase inhibition suppresses seizure susceptibility, but this effect has not been examined in the context of
AD. Therefore, major gaps in knowledge remain regarding the role of brain-derived estradiol (neuroestradiol) in
excitability, seizure susceptibility, and neuropathology in the comorbid relationship of seizures and AD. The
overall objective of the proposed studies is to determine the role of neuroestradiol in modulating cellular
excitability, synaptic transmission, and seizure susceptibility in a mouse model of AD that is prone to develop
seizures. In Aim 1, we will use patch clamp electrophysiology, biochemistry, multilabel immunofluorescence
microscopy, and a novel transgenic mouse model to determine the role of neuroestradiol in modulating cellular
excitability and synaptic transmission in the hippocampus in AD and control mice. In Aim 2, we will use in vivo
video-EEG and histological evaluation of neurodegeneration and gliosis to determine the role of neuroestradiol
in modulating seizure susceptibility and seizure-induced neuropathology in the context of AD. These studies will
have positive translational impact by providing new insights into the roles of neuroestradiol in hyperexcitability
and seizures in AD in both males and females, enabling development of new therapeutic strategies to maximize
seizure-suppressive effects while minimizing deleterious effects on cognition.