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Reduced gene expression of delta GABAA receptor subunits in circulating monocytes during the symptomatic luteal phase in premenstrual dysphoric disorder
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.ORCID iD: 0000-0002-9662-981X
Uppsala University, Uppsala, Sweden.
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.ORCID iD: 0000-0002-5697-4299
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.ORCID iD: 0000-0002-4988-1967
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Premenstrual dysphoric disorder (PMDD) has been hypothesized to be related to an abnormal sensitivity of the g-aminobutyric acid type A (GABAA) receptor to progesterone-derived neurosteroids. GABAA receptor sensitivity to neurosteroid-modulation is dependent on its subunit composition.

Methods: In the present study, we used quantitative reverse transcription polymerase chain reactions (RT-qPCR) to compare messenger ribonucleic acid (mRNA) expression of GABAA receptor subunits in peripheral mononuclear cells (PBMCs) across the menstrual cycle in 29 women with PMDD and 27 controls. We related mRNA subunit expression to serum levels of neurosteroids, and to functional activation of the amygdala, a key brain region involved in emotion generation, measured using functional magnetic resonance imaging (fMRI).

Results: Women with PMDD had lower mRNA expression of the delta GABAA receptor subunit during the luteal phase of the menstrual cycle. Lower delta mRNA expression was related to higher amygdala activation in PMDD women.

Conclusion: GABAA receptor incorporating the delta subunit are especially sensitive to neurosteroids modulation. It is possible that the mood symptoms of PMDD are mediated by an inability to effectively adjust the expression of this receptor type in response to neurosteroids fluctuations, leading to dysregulation GABAergic tone and increased activity in emotion-generating brain circuits.

National Category
Other Clinical Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
URN: urn:nbn:se:umu:diva-224450OAI: oai:DiVA.org:umu-224450DiVA, id: diva2:1858514
Available from: 2024-05-17 Created: 2024-05-17 Last updated: 2024-05-20
In thesis
1. Premenstrual dysphoric disorder: brain structure and function, GABAA-active neurosteroids and GABAA receptor plasticity
Open this publication in new window or tab >>Premenstrual dysphoric disorder: brain structure and function, GABAA-active neurosteroids and GABAA receptor plasticity
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background Premenstrual dysphoric disorder (PMDD) is an ovarian hormone-bound disorder, characterized by mood symptoms which occur exclusively during the luteal phase of the menstrual cycle. Previous neuroimaging studies of PMDD have primarily reported functional brain differences during the luteal phase in regions of the salience network (SN), which is commonly implicated in mood and anxiety disorders. SN dysfunction may mediate affective and behavioral deficits by leading to enhanced detection and inappropriate assignment of salience to stimuli. What drives altered brain function in PMDD is unknown. However, one influential hypothesis implicates the luteal phase hormone progesterone, and in particular its neurosteroid metabolites. Progesterone-derived neurosteroids increase transmission at the g- aminobutyric acid type A (GABAA) receptor, leading to increased inhibitory tone at the neuronal level. This thesis aimed to i) investigate structural and functional characteristics of the brain in PMDD, ii) relate functional measures to levels of neurosteroids during the luteal phase, and iii) investigate how gene expression of GABAA receptor subunits is altered across the menstrual cycle in PMDD.

Results In Study I, we found that women with PMDD had thinner cortices in widespread brain regions, including regions of the SN. In Studies II and III, we found that increases in functional brain measures are most prominent during the symptomatic luteal phase in regions belonging to the SN and in other networks commonly involved in the psychopathology of mood disorders. Furthermore, we could show that increased activity in key nodes of the SN was apparent in the follicular phase and related to the severity of affective symptoms experienced during the luteal phase. Additionally, in Study II, we found that functional activity in the amygdala, a key region of the SN, was differentially associated with serum levels of GABAA receptor- active neurosteroids between PMDD and controls during the luteal phase. Lastly, in Study IV, we found seminal evidence of reduced mRNA expression of the d-GABAA subunit, which imbues GABAA receptors with increased sensitivity to progesterone’s neurosteroid metabolites. Lower expression of d subunits was related to higher amygdala reactivity.

Conclusion In this thesis, I provide evidence for altered structure and function in multiple brain networks, particularly the SN in PMDD. Accentuated SN dysfunction during the symptomatic luteal phase may be mediated by the amygdala, and related to abnormal deficits in the expression of neurosteroid-sensitive d- GABAA receptors in response to ovarian hormone fluctuations.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. p. 128
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2310
Keywords
Premenstrual dysphoric disorder, GABAA receptor, neurosteroids, allopregnanolone, isoallopregnanolone, functional magnetic brain imaging, salience network
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-224452 (URN)978-91-8070-420-5 (ISBN)978-91-8070-419-9 (ISBN)
Public defence
2024-08-23, Bergasalen, Byggnad 27, Norrlands Universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2024-05-24 Created: 2024-05-17 Last updated: 2024-05-20Bibliographically approved

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Stiernman, LouiseJohansson, Inga-MajBixo, Marie

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