Regulation of synaptic plasticity in amygdala mediated by neuron-synthetized sexual hormones (sex neurosteroids)

• Applicants: Professor Dr. Roland A. Bender; Professorin Dr. Gabriele Maria Rune
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 384870444

• Final Report Year: 2024

Final Report Abstract

In the reported project, we aimed at characterizing the influence of sexual hormones on neuronal plasticity in the basolateral (BLA) and central (CeA) amygdala sexspecifically. For this purpose, we conducted behavior, electrophysiology and molecular biology analyses using genetically-modified mice and organotypic cultures. Preparatory studies were intended to use the hippocampus, which shows marked anatomical and physiological homologies to BLA, and results were later to be transfered to and scrutinized in the amygdala nuclei. We focussed early on the functions of GPER1, a membrane-bound estrogen receptor which mediates rapid estrogen signaling. We could show that GPER1 enforces the dendritic maturation in the developing hippocampus and modulates neuronal plasticity and physiology in the adult hippocampus, resulting in sex (and estrous cycle stage) -dependent memory deficits, if GPER1 is absent. We further observed behavior changes in GPER1-deficient mice, such as an increased fear conditioning in proestrus females, which strongly indicate sex-specific roles of GPER1 in the amygdala. As a side effect of these studies, we further identified a function of GPER1 for the migration of neuronal progenitors along the rostral migratory stream to the olfactory bulb. RESUME: Our intended goal – the characterization of sex hormone effects in amygdala – was only marginally reached by the project. Its major achievements concern the characterization of functions of GPER1, which was mainly accomplished for the hippocampus so far. Evidence for similar functions in the amygdala has emerged. However, the underlying mechanisms have not yet been resolved and some studies are still ongoing.

Publications

• Distal Dendritic Enrichment of HCN1 Channels in Hippocampal CA1 Is Promoted by Estrogen, but Does Not Require Reelin. eneuro, 5(5), ENEURO.0258-18.2018.
  Meseke, Maurice; Neumüller, Florian; Brunne, Bianka; Li, Xiaoyu; Anstötz, Max; Pohlkamp, Theresa; Rogalla, Meike M.; Herz, Joachim; Rune, Gabriele M. & Bender, Roland A.
  
• Sex hormones modulate pathogenic processes in experimental traumatic brain injury. Journal of Neurochemistry, 150(2), 173-187.
  Gölz, Christina; Kirchhoff, Florian Paul; Westerhorstmann, Jana; Schmidt, Matthias; Hirnet, Tobias; Rune, Gabriele M.; Bender, Roland A. & Schäfer, Michael K.E.
  
• GPER1 Signaling Initiates Migration of Female V-SVZ-Derived Cells. iScience, 23(5), 101077.
  Haumann, Iris; Sturm, Muriel Anne; Anstötz, Max & Rune, Gabriele M.
  
• Sex-specific Regulation of Spine Density and Synaptic Proteins by G-protein-coupled Estrogen Receptor (GPER)1 in Developing Hippocampus. Neuroscience, 472, 35-50.
  Li, Xiaoyu; Johann, Sonja; Rune, Gabriele M. & Bender, Roland A.
  
• A culture model for the assessment of phenylalanine neurotoxicity in phenylketonuria. In vitro models, 1(1), 103-114.
  Kylies, Julian; Brunne, Bianka & Rune, Gabriele M.
  
• Sex neurosteroidogenesis and hippocampal network maintenance. Current Opinion in Endocrine and Metabolic Research, 23, 100316.
  Brunne, Bianka & Rune, Gabriele M.
  
• Sex‐dependent responsiveness of hippocampal neurons to sex neurosteroids: A role of Arc/Arg3.1. Journal of Neuroendocrinology, 34(2).
  Brökling, Janina; Brunne, Bianka & Rune, Gabriele M.
  
• Effects of 24-hour oral estradiol-valerate administration on hormone levels in men and pre-menopausal women. Psychoneuroendocrinology, 156, 106320.
  Rune, Gabriele M.; Joue, Gina & Sommer, Tobias
  
• GPER1 deficiency causes sex-specific dysregulation of hippocampal plasticity and cognitive function. Journal of Endocrinology, 258(3).
  Koitmäe, Aune; Karsten, Yannik; Li, Xiaoyu; Morellini, Fabio; Rune, Gabriele M. & Bender, Roland A.
  
• Sexually differentiated microglia and CA1 hippocampal synaptic connectivity. Journal of Neuroendocrinology, 35(5).
  Prengel, Tim M.; Brunne, Bianka; Habiballa, Moataz & Rune, Gabriele M.
  
• Studying estrogen effects in an in vitro-model of traumatic brain injury (TBI). Brain Organoid and Systems Neuroscience Journal, 2, 31-42.
  Hemmat, Houman; Bongarts, Lisanne; Meiringer, Paula & Bender, Roland A.