Estrogen receptor beta in astrocytes modulates cognitive function in mid-age female mice

Noriko Itoh, Yuichiro Itoh, Cassandra E. Meyer, Timothy Takazo Suen, Diego Cortez-Delgado, Michelle Rivera Lomeli, Sophia Wendin, Sri Sanjana Somepalli, Lisa C. Golden, Allan MacKenzie-Graham and Rhonda R. Voskuhl ()
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Noriko Itoh: David Geffen School of Medicine at UCLA
Yuichiro Itoh: David Geffen School of Medicine at UCLA
Cassandra E. Meyer: David Geffen School of Medicine at UCLA
Timothy Takazo Suen: David Geffen School of Medicine at UCLA
Diego Cortez-Delgado: David Geffen School of Medicine at UCLA
Michelle Rivera Lomeli: David Geffen School of Medicine at UCLA
Sophia Wendin: David Geffen School of Medicine at UCLA
Sri Sanjana Somepalli: David Geffen School of Medicine at UCLA
Lisa C. Golden: David Geffen School of Medicine at UCLA
Allan MacKenzie-Graham: David Geffen School of Medicine at UCLA
Rhonda R. Voskuhl: David Geffen School of Medicine at UCLA

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Menopause is associated with cognitive deficits and brain atrophy, but the brain region and cell-specific mechanisms are not fully understood. Here, we identify a sex hormone by age interaction whereby loss of ovarian hormones in female mice at midlife, but not young age, induced hippocampal-dependent cognitive impairment, dorsal hippocampal atrophy, and astrocyte and microglia activation with synaptic loss. Selective deletion of estrogen receptor beta (ERβ) in astrocytes, but not neurons, in gonadally intact female mice induced the same brain effects. RNA sequencing and pathway analyses of gene expression in hippocampal astrocytes from midlife female astrocyte-ERβ conditional knock out (cKO) mice revealed Gluconeogenesis I and Glycolysis I as the most differentially expressed pathways. Enolase 1 gene expression was increased in hippocampi from both astrocyte-ERβ cKO female mice at midlife and from postmenopausal women. Gain of function studies showed that ERβ ligand treatment of midlife female mice reversed dorsal hippocampal neuropathology.

Date: 2023
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DOI: 10.1038/s41467-023-41723-7

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