Item Details

title

AGE, SEX, AND HORMONE-RELATED DIFFERENCES IN NMDAR FUNCTION: USING EEG TO UNDERSTAND POTENTIAL RISK FACTORS FOR SCHIZOPHRENIA

author

Holter, Kimberly Marie

abstract

The pathophysiology of schizophrenia varies tremendously depending on patient demographics (i.e. sex, age), yet the mechanisms contributing to this variability are not understood. For example, males generally have a more severe course of illness, though, in females, 17β-estradiol (E2) decline during menopause contributes to worsened symptoms and diminished response to antipsychotics including olanzapine. Thus, identifying ways to stratify populations in both preclinical and clinical studies is a vital next step in precision medicine. N-methyl-D-aspartate receptor (NMDAR) hypofunction underlies schizophrenia pathophysiology, and quantitative electroencephalography (qEEG) is a functional readout sensitive to NMDAR manipulation. Elevated resting-state gamma power has been identified in patients with schizophrenia and, similarly, following administration of NMDAR antagonists (i.e. MK-801). Thus, this dissertation used qEEG in rodents as a translational approach to evaluate how sex, age, and E2 levels influence NMDAR function. In Chapter II, MK-801 was administered to young and middle-aged male and female Sprague–Dawley rats implanted with wireless EEG transmitters. Interestingly, while other groups experienced elevations in gamma power, middle-aged female rats demonstrated a blunted response across all tested doses. As this age represents the onset of reproductive decline, hormonal factors may underlie this altered sensitivity. Chapter III expanded on this, evaluating changes in ovariectomized rats (Ovx) without or with E2 (Ovx+E). Ovx rats were more sensitive to MK-801-induced changes in gamma power compared to Ovx+E rats, demonstrating a leftward shift in the biphasic dose-response curve. Additionally, NMDARs have varying compositions of subunits including GluN2A and GluN2B; only GluN2A-preferring antagonists (i.e. PEAQX) increase gamma power. As hypothesized, Ovx rats also demonstrated increased sensitivity to PEAQX. This was complimented with findings of increased MK-801-induced attentional impairments and reduced synaptic GluN2A expression in the prefrontal cortex. Importantly, in Ovx rats, olanzapine was less effective in mitigating MK-801-induced elevations in gamma power. Instead, results support Group II metabotropic glutamate receptors as a novel therapeutic target in E2-deprived conditions. Altogether, these studies established a relationship between E2 and NMDAR function, suggesting E2 deprivation may serve as a risk factor for schizophrenia by exacerbating NMDAR hypofunction. These findings can ultimately be used to inform subpopulation-specific differences in therapeutic response.

subject

EEG

Estradiol

Gamma Band Power

MK-801

NMDAR

Schizophrenia

contributor

Gould, Robert W. (advisor)

Macauley-Rambach, Shannon L. (committee member)

Bimonte-Nelson, Heather A. (committee member)

Raab-Graham, Kimberly F. (committee member)

Weiner, Jeffrey L. (committee member)

date

2024-09-13T08:36:37Z (accessioned)

2025-03-12T08:30:08Z (available)

2024 (issued)

degree

Physiology and Pharmacology (discipline)

embargo

2025-03-12 (terms)

identifier

http://hdl.handle.net/10339/109857 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation