The goal of the proposed studies is to address fundamental processes underlying the changes in neuronal excitability in the female brain during periods of altered steroid hormone levels. We will explore the mechanisms governing changes in GABAergic inhibition during the ovarian cycle, pregnancy, and during the interaction between stress and the ovarian cycle. Our experiments will focus on the regulation of GABAAR expression and function by progesterone and its neurosteroid metabolites. We recently demonstrated dynamic, ovarian cycle-linked modifications in specific GABAAR expression and function, while others have shown the same receptors to parallel ovarian cycle changes in the periaqueductal grey matter or to be upregulated in a steroid withdrawal model of PMS. During diestrus in mice when levels of progesterone and of progesterone-derivatives neurosteroids are elevated, there is an increased expression: of the GABAAR 6 subunits in hippocampal neurons and an increase in GABAAR 6 subunit-mediated tonic inhibition in dentate gyrus granule cells (DGGCs). This increase in GABAAR 6 subunits corresponds to a period of lowered seizure susceptibility and anxiety.
The specific aims of this project will extend these Findings to the study of GABAAR alterations during pregnancy/postpartum and to the interactions between stress and the ovarian cycle. The fractional contributions of progesterone and its derivatives to the regulation of GABAAR expression and function will be addressed and possible molecular mechanisms (local receptor synthesis and receptor internalization) underlying the changes affecting the GABAergic system will be studied. A novel mouse model of postpartum depression will constitute a unique opportunity to begin to study fundamental neuronal mechanisms underlying this psychiatric disorder affecting nearly 10% of women in early motherhood. Our general hypothesis is that physiological and pathological changes in endogenous steroid hormones in the female brain alter neuronal excitability by producing hormonal state-dependent changes in specific neurotransmitter receptor systems. The focus of the present proposal is GABAergic inhibition in general, and specifically the tonic inhibition mediated by 6 subunit-containing GABAARs, which are the preferred, if not the sole, site mediating neurosteroid sensitivity in the CNS. The project will address the role of endogenous progesterone in GABAAR expression and function in female mice and will identify mechanisms underlying steroid hormone-linked changes in GABAARs by using a variety of molecular biological, biochemical, electrophysiological and behavioral approaches. Our studies are relevant to understanding the pathology of several psychiatric and neurological disorders including pre-menstrual dysphoric disorder (PMDD), catamenial epilepsy, and postpartum depression that are all linked to alterations in hormone levels in women. Uncovering events controlling the hormone-mediated regulation of GABAARs in females will lead to novel and potentially more effective therapeutic targets for treating and ultimately preventing these neurological and psychiatric disorders, while opening the way for fresh approaches to functional and clinical studies in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH076994-05
Application #
8106085
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Desmond, Nancy L
Project Start
2007-08-01
Project End
2012-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2011
Total Cost
$320,353
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Maguire, Jamie; Mody, Istvan (2016) Behavioral Deficits in Juveniles Mediated by Maternal Stress Hormones in Mice. Neural Plast 2016:2762518
Chen, L; Faas, G C; Ferando, I et al. (2015) Novel insights into the behavioral analysis of mice subjected to the forced-swim test. Transl Psychiatry 5:e551
Barth, Albert M I; Ferando, Isabella; Mody, Istvan (2014) Ovarian cycle-linked plasticity of ?-GABAA receptor subunits in hippocampal interneurons affects ? oscillations in vivo. Front Cell Neurosci 8:222
Ferando, Isabella; Mody, Istvan (2014) Interneuronal GABAA receptors inside and outside of synapses. Curr Opin Neurobiol 26:57-63
Engel Jr, Jerome; Thompson, Paul M; Stern, John M et al. (2013) Connectomics and epilepsy. Curr Opin Neurol 26:186-94
Brickley, Stephen G; Mody, Istvan (2012) Extrasynaptic GABA(A) receptors: their function in the CNS and implications for disease. Neuron 73:23-34
Gehman, Lauren T; Stoilov, Peter; Maguire, Jamie et al. (2011) The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain. Nat Genet 43:706-11
Maguire, Jamie; Ferando, Isabella; Simonsen, Charlotte et al. (2009) Excitability changes related to GABAA receptor plasticity during pregnancy. J Neurosci 29:9592-601
Maguire, Jamie; Mody, Istvan (2009) Steroid hormone fluctuations and GABA(A)R plasticity. Psychoneuroendocrinology 34 Suppl 1:S84-90
Belelli, Delia; Harrison, Neil L; Maguire, Jamie et al. (2009) Extrasynaptic GABAA receptors: form, pharmacology, and function. J Neurosci 29:12757-63

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