title: G-protein-coupled estrogen receptor 1 is anatomically positioned to modulate synaptic plasticity in the mouse hippocampus.
abstract: Both estrous cycle and sex affect the numbers and types of neuronal and glial profiles containing the classical estrogen receptors α and β, and synaptic levels in the rodent dorsal hippocampus. Here, we examined whether the membrane estrogen receptor, G-protein-coupled estrogen receptor 1 (GPER1), is anatomically positioned in the dorsal hippocampus of mice to regulate synaptic plasticity. By light microscopy, GPER1-immunoreactivity (IR) was most noticeable in the pyramidal cell layer and interspersed interneurons, especially those in the hilus of the dentate gyrus. Diffuse GPER1-IR was found in all lamina but was most dense in stratum lucidum of CA3. Ultrastructural analysis revealed discrete extranuclear GPER1-IR affiliated with the plasma membrane and endoplasmic reticulum of neuronal perikarya and dendritic shafts, synaptic specializations in dendritic spines, and clusters of vesicles in axon terminals. Moreover, GPER1-IR was found in unmyelinated axons and glial profiles. Overall, the types and amounts of GPER1-labeled profiles were similar between males and females; however, in females elevated estrogen levels generally increased axonal labeling. Some estradiol-induced changes observed in previous studies were replicated by the GPER agonist G1: G1 increased PSD95-IR in strata oriens, lucidum, and radiatum of CA3 in ovariectomized mice 6 h after administration. In contrast, estradiol but not G1 increased Akt phosphorylation levels. Instead, GPER1 actions in the synapse may be due to interactions with synaptic scaffolding proteins, such as SAP97. These results suggest that although estrogen's actions via GPER1 may converge on the same synaptic elements, different pathways are used to achieve these actions.
authors: Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10065, ewaters@rockfeller.edu.
authors: Elizabeth M
authors: EM
authors: Waters
authors: Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10065, Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065.
authors: Louisa I
authors: LI
authors: Thompson
authors: Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065.
authors: Parth
authors: http://orcid.org/0000-0003-4947-2976
authors: P
authors: Patel
authors: Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065.
authors: Andreina D
authors: http://orcid.org/0000-0002-5085-072X
authors: AD
authors: Gonzales
authors: Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065.
authors: Hector Zhiyu
authors: HZ
authors: Ye
authors: Department of Medicine, Brown University, Providence, Rhode Island 02903, and.
authors: Edward J
authors: EJ
authors: Filardo
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
authors: Deborah J
authors: DJ
authors: Clegg
authors: Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10065.
authors: Jolanta
authors: J
authors: Gorecka
authors: Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10065.
authors: Keith T
authors: KT
authors: Akama
authors: Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10065.
authors: Bruce S
authors: BS
authors: McEwen
authors: Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10065, Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065.
authors: Teresa A
authors: http://orcid.org/0000-0002-0458-6569
authors: TA
authors: Milner
mesh_terms: D000818:Animals; D000074288:Discs Large Homolog 1 Protein; D000076122:Disks Large Homolog 4 Protein; D030762:Estrous Cycle / Q000502:physiology; D005260:Female; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017661:Receptors, Presynaptic / Q000378:metabolism / Q000648:ultrastructure; D012727:Sex Characteristics; D013569:Synapses / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure*
chemical_list: D000074288:Discs Large Homolog 1 Protein; D000076122:Disks Large Homolog 4 Protein; C000614189:Dlg1 protein, mouse; C501447:Dlg4 protein, mouse; C532507:GPER1 protein, mouse; D008565:Membrane Proteins; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D017661:Receptors, Presynaptic; D051057:Proto-Oncogene Proteins c-akt; D051528:Guanylate Kinases
keywords: G-protein-coupled receptors; estrogen; estrogen receptors; estrous cycle; sex differences