G-protein-coupled estrogen receptor 1 is anatomically positioned to modulate synaptic plasticity in the mouse hippocampus

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), i...

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Published in:	The Journal of neuroscience Vol. 35; no. 6; pp. 2384 - 2397
Main Authors:	Waters, Elizabeth M, Thompson, Louisa I, Patel, Parth, Gonzales, Andreina D, Ye, Hector Zhiyu, Filardo, Edward J, Clegg, Deborah J, Gorecka, Jolanta, Akama, Keith T, McEwen, Bruce S, Milner, Teresa A
Format:	Journal Article
Language:	English
Published:	United States Society for Neuroscience 11-02-2015
Subjects:	Animals Discs Large Homolog 1 Protein Disks Large Homolog 4 Protein Estrous Cycle - physiology Female Guanylate Kinases - genetics Guanylate Kinases - metabolism Hippocampus - drug effects Hippocampus - physiology Hippocampus - ultrastructure Male Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Inbred C57BL Mice, Knockout Neuronal Plasticity - drug effects Neuronal Plasticity - genetics Neuronal Plasticity - physiology Proto-Oncogene Proteins c-akt - metabolism Receptors, Estrogen Receptors, G-Protein-Coupled - drug effects Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Receptors, Presynaptic - metabolism Receptors, Presynaptic - ultrastructure Sex Characteristics Synapses - drug effects Synapses - physiology Synapses - ultrastructure estrogen estrous cycle estrogen receptors G-protein-coupled receptors sex differences
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 B.S.M. and T.A.M. contributed equally to this work. Author contributions: E.M.W., K.T.A., B.S.M., and T.A.M. designed research; E.M.W., L.I.T., P.P., A.G., H.Z.Y., J.G., K.T.A., and T.A.M. performed research; E.J.F. and D.C. contributed unpublished reagents/analytic tools; E.M.W., L.I.T., J.G., K.T.A., and T.A.M. analyzed data; E.M.W. and T.A.M. wrote the paper.
ISSN:	0270-6474 1529-2401
DOI:	10.1523/jneurosci.1298-14.2015