Estrogen Depletion Alters Cortical NMDAR Function in Ovariectomized Rats

Abstract

<b>Abstract ID 20567</b> <b>Poster Board 373</b> Despite similar overall prevalence of schizophrenia diagnoses in males and females, &gt;75% of patients diagnosed between 45-50 years of age are female, an age range that corresponds with the menopause transition. Evidence suggests that decreased circulating estrogen associated with menopause may contribute to this late stage onset in females. For example, perimenopausal and postmenopausal women exhibit heightened symptom severity, risk of relapse, and poorer treatment response to some antipsychotic medications compared to premenopausal women. However, mechanisms contributing to these alterations are not well understood. Administration of <i>N</i>-methyl-D-aspartate receptor (NMDAR) antagonists, including MK-801, is frequently used to disrupt cognition and induce hyperlocomotion, modelling the cognitive and positive symptoms of schizophrenia, respectively, in animals. MK-801 also induces excessive increases in high frequency gamma power recorded via electroencephalography (EEG) which corresponds with cognitive disruptions and positive symptoms. Gamma power reflects a balance of coritcal GABA and glutamate signaling and, thus, these increases are hypothesized to be driven by inhibition of NMDARs on cortical PV-containing interneurons. This ultimately causes disinhibition of glutamatergic pyramidal neurons and increased excitability. Oscillations within the beta frequency range are also altered in schizophrenia and are sensitive to inhibition of NMDARs on PV-containing interneurons. Beta power is commonly reduced following NMDAR antagonist administration in rodents and humans and corresponds with cognitive impairment. However, few preclinical studies have examined the influence of hormones including 17β-estradiol (E2), the most potent form of circulating estrogen, in conjunction with the NMDAR antagonist model. Using surface electrodes and wireless EEG detection, we directly tested the hypothesis that E2 depletion reduces NMDAR function and increases associated cognitive impairments. MK-801 (0.03-0.18 mg/kg, sc) was administered to 3-month-old female rats who were ovariectomized (Ovx; a rodent model of surgical menopause) and implanted with an empty silastic capsule (Ovx rats) or a capsule containing E2, a well-established method of chronic E2 delivery (Ovx+E rats). Data suggests, while there are no significant baseline differences, Ovx rats are more sensitive to MK-801-induced changes in gamma and beta power compared to Ovx+E rats. Ongoing studies are examining the ability of olanzapine (0.3-1.8 mg/kg, IP), an atypical antipsychotic, to attenuate MK-801-induced functional EEG changes. We also investigated cognitive performance of Ovx and Ovx+E rats on a touchscreen paired-associates learning (PAL) task to evaluate visual learning and working memory. While MK-801 dose-dependently decreased accuracy, no significant differences were noted between Ovx and Ovx+E groups. Ongoing studies are assessing other cognitive domains (attention and vigilance) using the touchscreen 5-choice serial reaction time task. Ultimately, these studies aim to establish a relationship between estradiol, NMDAR function, and antipsychotic-like activity using a translational biomarker of brain function to inform menopause-related differences in patients with schizophrenia to pursue development of novel antipsychotic medications. <b>Support/Funding Information:</b> AG077271 (R21)