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 ␣ and ␤, 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.

Emerging roles for the novel estrogen-sensing receptor GPER1 in the CNS

“…Thus there is growing evidence that GPER1 is well positioned to mediate the rapid non-genomic effects of E2 on dendritic spine morphology and function. Although most evidence points to a postsynaptic locus for GPER1, recent ultrastructural analyses has also found GPER1 expression at presynaptic terminals and in glia cells (Waters et al, 2015). Identification of GPER1-positive immunolabelling within presynaptic terminals suggests a possible role for GPER1 in regulating neurotransmitter release mechanisms.…”

“…Ultrastructural analyses have revealed that GPER1 expression is not only restricted to extranuclear sites within the dorsal striatum, but also that GPER1 is highly localised to dendritic spines (Almey et al, 2012). Similarly in hippocampal CA1 neurons, GPER1 immunoreactivity is associated with dendritic spines and is specifically localised to the postsynaptic density (PSD; Akama et al, 2013;Waters et al, 2015). Dual-labelling studies in cortical neurons also suggest synaptic expression of GPER1 as GPER1-positive immunolabelling colocalises with the presynaptic protein, bassoon (Srivastava and Evans, 2013).…”

“…Moreover the cellular localisation of GPER1 and the density of G proteins in specific cell types are thought to markedly influence GPER1 pharmacology (Srivastava and Evans, 2013). Recent studies suggest that GPER1 may associate with other GPCRs, such as the corticotropin releasing hormone receptor (Akama et al, 2013), or form receptor complexes with scaffolding proteins like SAP97 and PSD-95 (Waters et al, 2015;Akama et al, 2013), which is also likely to impact on GPER1 pharmacology.…”

“…However recent evidence suggests that GPER1 may also play a role (Akama et al, 2013;Waters et al, 2015). Indeed, in hippocampal neurons GPER1 positive-immunoreactivity is associated with dendritic spines and is localised to the postsynaptic density (PSD; Waters et al, 2015). Moreover, in biochemical assays the Cterminal domain of GPER1 binds to PDZ domains of the spine scaffolding protein PSD-95 (Akama et al, 2013).…”

“…Moreover, in biochemical assays the Cterminal domain of GPER1 binds to PDZ domains of the spine scaffolding protein PSD-95 (Akama et al, 2013). In addition, GPER1 has been shown to co-immunoprecipitate with SAP97 (Waters et al, 2015), a postsynaptic scaffolding protein that is linked to recycling of receptors within dendritic spines (Magalhaes et al, 2012). Thus there is growing evidence that GPER1 is well positioned to mediate the rapid non-genomic effects of E2 on dendritic spine morphology and function.…”