GABA-A Receptor Subunit Gene Expression as a Biomarker for Perimenstrual Change in Affect and Suicidality

The fluctuating ovarian hormones of the menstrual cycle can influence affective symptoms, with effects ranging from mild, short-term mood changes to severe, debilitating psychiatric symptoms and suicidal ideation (SI). Clinically significant presentations of this phenomenon are prevalent: over half of reproductive-aged females with chronic psychopathology experience menstrual cycle affective change (MCAC) of their underlying symptoms, and 5-10% of females meet strict criteria for Premenstrual Dysphoric Disorder (PMDD). MCAC has long been understood as an abnormal neurobiological sensitivity to normal post-ovulatory fluctuations of estradiol and progesterone, but the pathophysiologic causes of this neurobiological sensitivity remain unknown. Altered GABAergic neurotransmission due to aberrant interactions between the GABA-A receptor and progesterone-derived neuroactive steroids represents a compelling candidate mechanism of MCAC. Briefly, progesterone and its neuroactive steroid metabolites modulate inhibitory neurotransmission via action at the GABA-A receptor (GABAAR), and these neuroactive steroid metabolites are normal in in MCAC. The composition of GABAAR subunits within the receptor determines its activity (e.g., sensitivity to modulation and subsequent strength of inhibitory current), suggesting that receptor plasticity, as indexed by GABAAR subunits, may be the source of this abnormal sensitivity to normal ovarian hormone flux. Thus, our central hypothesis is that dysregulated trajectories of GABAAR subunit expression across the menstrual cycle lead to MCAC by altering the brain’s responses to normal cyclical hormone changes. This hypothesis has long been suggested by cellular and animal models but has never been tested in humans. In the present dissertation, we test this hypothesis for the first time in a longitudinal clinical study by measuring 1) symptom trajectories across the menstrual cycle, 2) GABAAR subunit gene expression trajectories across the menstrual cycle, and 3) the relationship between psychiatric symptom trajectories and GABAAR subunit trajectories. We collected daily symptom ratings across two menstrual cycles in addition to five blood samples at precise, menstrual cycle-timed visits to collect RNA for peripheral gene expression of three GABAAR subunit genes (GABRD, GABRG2, and GABRA5), each with unique relationships to hormonal regulation and affect-related outcomes. Participants included psychiatric outpatients with past month SI and healthy controls (with no present psychiatric diagnoses). First, we found that the categorical grouping of participants by MCAC status was not a stable metric between repeated cycles and did not accurately differentiate those with and without clinically significant levels of psychiatric symptoms. We propose that continuous, multidimensional measures of MCAC are a better fit for longitudinal data, do not require assumptions of test-retest reliability, and significantly improve power. We then analyzed peripheral GABAAR subunit gene expression across the menstrual cycle and found that gene expression fluctuates notably within-person, GABRG2 expression is suppressed with high P4, and all three genes are characterized by significant individual differences in trajectory across the menstrual cycle. Lastly, we discovered that indices of peripheral GABAAR subunit gene expression over time predict menstrual cycle-related fluctuations in anxiety, irritability, and SI. Specifically, we observed that both mean levels of GABRG2 gene expression and exposure to change over time in the GABRG2 gene predict varying trajectories of anxiety, irritability, and SI. We found similar but less robust relationships between the GABRA5 gene, anxiety, and SI. There are no current biomarkers for MCAC, and thus these findings propose a possible novel biomarker for MCAC that can be measured peripherally for potential diagnosis and treatment. Together, this dissertation comprises a novel, translational study, demonstrating for the first time that gene expression for GABAA receptor subunits may be a biomarker for affective symptom cyclicity across the menstrual cycle.

Author dc:creator

• Jordan Christina Barone (24399068)

• Biology, Neuroscience
• Psychology, Clinical

Statement dc:rights

• In Copyright

DOI dc:identifier

https://doi.org/10.25417/uic.32993699.v1

OAI identifier oai:identifier

oai:figshare.com:article/32993699