Sex-specific Regulation of Spine Density and Synaptic Proteins by G-protein-coupled Estrogen Receptor (GPER)1 in Developing Hippocampus

TY - JOUR

T1 - Sex-specific Regulation of Spine Density and Synaptic Proteins by G-protein-coupled Estrogen Receptor (GPER)1 in Developing Hippocampus

AU - Li, Xiaoyu

AU - Johann, Sonja

AU - Rune, Gabriele M

AU - Bender, Roland A

N1 - Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.

PY - 2021/9/15

Y1 - 2021/9/15

N2 - G-protein-coupled-estrogen-receptor 1 (GPER1) is a membrane-bound receptor that mediates estrogen signaling via intracellular signaling cascades. We recently showed that GPER1 promotes the distal dendritic enrichment of hyperpolarization activated and cyclic nucleotide-gated (HCN)1 channels in CA1 stratum lacunosum-moleculare (SLM), suggesting a role of GPER1-mediated signaling in neuronal plasticity. Here we studied whether this role involves processes of structural plasticity, such as the regulation of spine and synapse density in SLM. In organotypic entorhino-hippocampal cultures from mice expressing eGFP, we analyzed spine densities in SLM after treatment with GPER1 agonist G1 (20 nM). G1 significantly increased the density of "non-stubby" spines (maturing spines with a spine head and a neck), but did so only in cultures from female mice. In support of this finding, the expression of synaptic proteins was sex-specifically altered in the cultures: G1 increased the protein (but not mRNA) expression of PSD95 and reduced the p-/n-cofilin ratio only in cultures from females. Application of E2 (2 nM) reproduced the sex-specific effect on spine density in SLM, but only partially on the expression of synaptic proteins. Spine synapse density was, however, not altered after G1-treatment, suggesting that the increased spine density did not translate into an increased spine synapse density in the culture model. Taken together, our results support a role of GPER1 in mediating structural plasticity in CA1 SLM, but suggest that in developing hippocampus, this role is sex-specific.

AB - G-protein-coupled-estrogen-receptor 1 (GPER1) is a membrane-bound receptor that mediates estrogen signaling via intracellular signaling cascades. We recently showed that GPER1 promotes the distal dendritic enrichment of hyperpolarization activated and cyclic nucleotide-gated (HCN)1 channels in CA1 stratum lacunosum-moleculare (SLM), suggesting a role of GPER1-mediated signaling in neuronal plasticity. Here we studied whether this role involves processes of structural plasticity, such as the regulation of spine and synapse density in SLM. In organotypic entorhino-hippocampal cultures from mice expressing eGFP, we analyzed spine densities in SLM after treatment with GPER1 agonist G1 (20 nM). G1 significantly increased the density of "non-stubby" spines (maturing spines with a spine head and a neck), but did so only in cultures from female mice. In support of this finding, the expression of synaptic proteins was sex-specifically altered in the cultures: G1 increased the protein (but not mRNA) expression of PSD95 and reduced the p-/n-cofilin ratio only in cultures from females. Application of E2 (2 nM) reproduced the sex-specific effect on spine density in SLM, but only partially on the expression of synaptic proteins. Spine synapse density was, however, not altered after G1-treatment, suggesting that the increased spine density did not translate into an increased spine synapse density in the culture model. Taken together, our results support a role of GPER1 in mediating structural plasticity in CA1 SLM, but suggest that in developing hippocampus, this role is sex-specific.

KW - Animals

KW - Dendritic Spines/metabolism

KW - Female

KW - GTP-Binding Proteins

KW - Hippocampus/metabolism

KW - Male

KW - Mice

KW - Receptors, Estrogen/metabolism

KW - Receptors, G-Protein-Coupled

KW - Synapses/metabolism

U2 - 10.1016/j.neuroscience.2021.07.035

DO - 10.1016/j.neuroscience.2021.07.035

M3 - SCORING: Journal article

C2 - 34364953

VL - 472

SP - 35

EP - 50

JO - NEUROSCIENCE

JF - NEUROSCIENCE

SN - 0306-4522

ER -