TY - JOUR
T1 - Cnih3 Deletion Dysregulates Dorsal Hippocampal Transcription across the Estrous Cycle
AU - Mulvey, Bernard
AU - Frye, Hannah E.
AU - Lintz, Tania
AU - Fass, Stuart
AU - Tycksen, Eric
AU - Nelson, Elliot C.
AU - Morón, Jose A.
AU - Dougherty, Joseph D.
N1 - Publisher Copyright:
© 2023 Mulvey et al.
PY - 2023/3
Y1 - 2023/3
N2 - In females, the hippocampus, a critical brain region for coordination of learning, memory, and behavior, displays altered physiology and behavioral output across the estrous or menstrual cycle. However, the molecular effectors and cell types underlying these observed cyclic changes have only been partially characterized to date. Recently, profiling of mice null for the AMPA receptor trafficking gene Cnih3 have demonstrated estrous-dependent phenotypes in dorsal hippocampal synaptic plasticity, composition, and learning/memory. We therefore profiled dorsal hippocampal transcriptomes from female mice in each estrous cycle stage, and contrasted it with that of males, across wild-type (WT) and Cnih3 mutants. In wild types, we identified only subtle differences in gene expression between the sexes, while comparing estrous stages to one another revealed up to .1000 differentially expressed genes (DEGs). These estrous-responsive genes are especially enriched in gene markers of oligodendrocytes and the dentate gyrus, and in functional gene sets relating to estrogen response, potassium channels, and synaptic gene splicing. Surprisingly, Cnih3 knock-outs (KOs) showed far broader transcriptomic differences between estrous cycle stages and males. Moreover, Cnih3 knock-out drove subtle but extensive expression changes accentuating sex differential expression at diestrus and estrus. Altogether, our profiling highlights cell types and molecular systems potentially impacted by estrous-specific gene expression patterns in the adult dorsal hippocampus, enabling mechanistic hypothesis genera-tion for future studies of sex-differential neuropsychiatric function and dysfunction. Moreover, these findings suggest an unrecognized role of Cnih3 in buffering against transcriptional effects of estrous, providing a candidate molecular mechanism to explain estrous-dependent phenotypes observed with Cnih3 loss.
AB - In females, the hippocampus, a critical brain region for coordination of learning, memory, and behavior, displays altered physiology and behavioral output across the estrous or menstrual cycle. However, the molecular effectors and cell types underlying these observed cyclic changes have only been partially characterized to date. Recently, profiling of mice null for the AMPA receptor trafficking gene Cnih3 have demonstrated estrous-dependent phenotypes in dorsal hippocampal synaptic plasticity, composition, and learning/memory. We therefore profiled dorsal hippocampal transcriptomes from female mice in each estrous cycle stage, and contrasted it with that of males, across wild-type (WT) and Cnih3 mutants. In wild types, we identified only subtle differences in gene expression between the sexes, while comparing estrous stages to one another revealed up to .1000 differentially expressed genes (DEGs). These estrous-responsive genes are especially enriched in gene markers of oligodendrocytes and the dentate gyrus, and in functional gene sets relating to estrogen response, potassium channels, and synaptic gene splicing. Surprisingly, Cnih3 knock-outs (KOs) showed far broader transcriptomic differences between estrous cycle stages and males. Moreover, Cnih3 knock-out drove subtle but extensive expression changes accentuating sex differential expression at diestrus and estrus. Altogether, our profiling highlights cell types and molecular systems potentially impacted by estrous-specific gene expression patterns in the adult dorsal hippocampus, enabling mechanistic hypothesis genera-tion for future studies of sex-differential neuropsychiatric function and dysfunction. Moreover, these findings suggest an unrecognized role of Cnih3 in buffering against transcriptional effects of estrous, providing a candidate molecular mechanism to explain estrous-dependent phenotypes observed with Cnih3 loss.
KW - candidate gene
KW - gene expression
KW - opioid use disorder
KW - sex differences
KW - sex hormones
UR - http://www.scopus.com/inward/record.url?scp=85150180968&partnerID=8YFLogxK
U2 - 10.1523/ENEURO.0153-22.2023
DO - 10.1523/ENEURO.0153-22.2023
M3 - Article
C2 - 36849260
AN - SCOPUS:85150180968
SN - 2373-2822
VL - 10
JO - eNeuro
JF - eNeuro
IS - 3
M1 - ENEURO.0153-22.2023
ER -