Membrane-Initiated Estradiol Signaling Induces Spinogenesis Required for Female Sexual Receptivity

Abstract

Estrogens have profound actions on the structure of the nervous system during development and in adulthood. One of the signature actions of estradiol is to alter the morphology of neural processes. In the hippocampus, estradiol modulates spines and cellular excitability that affect cognitive behaviors. In the hypothalamus, estradiol increases spine density in mediobasal hypothalamic nuclei that regulate reproduction. The hypothalamic arcuate nucleus (ARH), an important site for modulation of female sexual receptivity, has a sexual dimorphism in dendritic spine density that favors females. In the present study, we used both ␤-actin immunostaining and Golgi staining to visualize estradiol-induced changes in spine density in Long-Evans rats. Golgi impregnation was used to visualize spine shape, and then ␤-actin immunoreactivity was used as a semiquantitative measure of spine plasticity since actin forms the core of dendritic spines. At 4 h after estradiol treatment, both ␤-actin immunofluorescence and filopodial spines were increased (from 70.57 Ϯ 1.09% to 78.01 Ϯ 1.05%, p Ͻ 0.05). Disruption of estradiol-induced ␤-actin polymerization with cytochalasin D attenuated lordosis behavior, indicating the importance of estradiol-mediated spinogenesis for female sexual receptivity (81.43 Ϯ 7.05 to 35.00 Ϯ 11.76, p Ͻ 0.05). Deactivation of cofilin, an actin depolymerizing factor is required for spinogenesis. Membrane-initiated estradiol signaling involving the metabotropic glutamate receptor 1a was responsible for the phosphorylation and thereby deactivation of cofilin. These data demonstrate that estradiolinduced spinogenesis in the ARH is an important cellular mechanism for the regulation of female sexual behavior.

Rapid effects of the G-protein coupled oestrogen receptor (GPER) on learning and dorsal hippocampus dendritic spines in female mice

“…That spine length would not be affected by G-1 in the present study is also consistent with previous studies showing that 17β-estradiol and PPT did not affect dendritic spine length [2][3]. It is possible that with a longer exposure to the treatments, an effect on spine length would also be found [29,30]. Together, these findings show that the actions of GPER agonist, G-1, along with ERα agonist, PPT, are consistent with the rapid effects of 17β-estradiol on dendritic spine density in the hippocampus.…”

Estrogen-Induced Memory Enhancements Are Blocked by Acute Bisphenol A in Adult Female Rats: Role of Dendritic Spines

“…More pertinent to the current study is that synaptic changes occur within minutes to hours (39) after E2, spine density has been shown to increase 4 h after E2 in the arcuate nucleus (58), and BPA rapidly inhibits E2-dependent increases in hippocampal spine synapse density (20). However, whether alterations in spines underlie changes in memory seen after E2 and/or BPA remains unclear.…”

Orphanin FQ-ORL-1 Regulation of Reproduction and Reproductive Behavior in the Female

“…1; reviewed in Micevych & Sinchak, 2013;Sinchak & Wagner, 2012). All of the steroid priming paradigms that facilitate lordosis converge to regulate the output of ARH β-endorphin (β-END) neurons that project to the MPN (Borgquist et al, 2013(Borgquist et al, , 2014Cheung & Hammer, 1995;Christensen, Dewing, & Micevych, 2011;Christensen & Micevych, 2012Dewing et al, 2007;Dewing, Christensen, Bondar, & Micevych, 2008;Long, Chhorvann, & Sinchak, 2012;Long et al, 2013Long et al, , 2014Micevych, Rissman, Gustafsson, & Sinchak, 2003;Mills, Sohn, & Micevych, 2004;Sanathara et al, 2011Sanathara et al, , 2014Sinchak et al, 2013;Sinchak & Micevych, 2001;Sinchak, Shahedi, Dewing, & Micevych, 2005; Fig. 1).…”

“…This rapid estradiol-induced MPN MOP activation that inhibits lordosis is produced by estradiol binding to extranuclear ERα trafficked to the plasma membrane (mERα) that complex to and signal through metabotropic glutamate receptors-type 1a (mGluR1a; mERα-mGluR1a; Fig. 1; Boulware, Kordasiewicz, & Mermelstein, 2007;Christensen et al, 2011;Dewing et al, 2007Dewing et al, , 2008Dominguez, Dewing, Kuo, & Micevych, 2013;Mills et al, 2004;Sanathara et al, 2014). The mERα-mGluR1a signaling in the ARH stimulates the release of neuropeptide Y (NPY) that acts on NPY-Y1 receptors in ARH β-END neurons to stimulate the release of β-END in MPN Mills et al, 2004;Sanathara et al, 2014).…”

“…1; Eckersell et al, 1998;Long et al, 2013Long et al, , 2014Sinchak & Micevych, 2001). MPN MOP deactivation after estradiol priming is an important step in the facilitation of lordosis (AcostaMartinez & Etgen, 2002;Christensen et al, 2011;Dewing et al, 2007;Eckersell et al, 1998;Kelly, Lagrange, Wagner, & Ronnekleiv, 1999;Sinchak & Micevych, 2001). Further, MPN MOP activation fluctuates in association with the state of sexual receptivity throughout the estrous cycle .…”