Dorsal Hippocampal Actin Polymerization Is Necessary for Activation of G-Protein-Coupled Estrogen Receptor (GPER) to Increase CA1 Dendritic Spine Density and Enhance Memory Consolidation

Abstract

Activation of the membrane estrogen receptor G-protein-coupled estrogen receptor (GPER) in ovariectomized mice via the GPER agonist G-1 mimics the beneficial effects of 17␤-estradiol (E 2 ) on hippocampal CA1 spine density and memory consolidation, yet the cellsignaling mechanisms mediating these effects remain unclear. The present study examined the role of actin polymerization and c-Jun N-terminal kinase (JNK) phosphorylation in mediating effects of dorsal hippocampally infused G-1 on CA1 dendritic spine density and consolidation of object recognition and spatial memories in ovariectomized mice. We first showed that object learning increased apical CA1 spine density in the dorsal hippocampus (DH) within 40 min. We then found that DH infusion of G-1 increased both CA1 spine density and phosphorylation of the actin polymerization regulator cofilin, suggesting that activation of GPER may increase spine morphogenesis through actin polymerization. As with memory consolidation in our previous work (Kim et al., 2016), effects of G-1 on CA1 spine density and cofilin phosphorylation depended on JNK phosphorylation in the DH. Also consistent with our previous findings, E 2 -induced cofilin phosphorylation was not dependent on GPER activation. Finally, we found that infusion of the actin polymerization inhibitor, latrunculin A, into the DH prevented G-1 from increasing apical CA1 spine density and enhancing both object recognition and spatial memory consolidation. Collectively, these data demonstrate that GPER-mediated hippocampal spinogenesis and memory consolidation depend on JNK and cofilin signaling, supporting a critical role for actin polymerization in the GPER-induced regulation of hippocampal function in female mice.

Estrogens in schizophrenia: progress, current challenges and opportunities

“…1 ) [ 22 ▪ ]. GPERs are for example highly expressed in hippocampal neurons where they activate pathways involved in cognitive functioning [ 23 ].…”

G Protein-Coupled Estrogen Receptor: Rapid Effects on Hippocampal-Dependent Spatial Memory and Synaptic Plasticity

“…The enhancement of memory was not due to activation of the extracellular signal-regulated kinase signaling normally observed following E2 treatment. Rather, GPER activation was associated with phosphorylation of c-Jun N-terminal, cofilin-mediated actin polymerization, and spinogenesis in region CA1 (55,57). Overall, these studies provide strong evidence that like E2, activation of GPER can facilitate hippocampal-dependent memory performance.…”

“…Interestingly, Oberlander and Woolley demonstrated that GPERinduced potentiation of excitatory synaptic responses in CA1 hippocampal pyramidal neurons is restricted to females and involves postsynaptic mechanisms (61). The role of GPER in synaptic plasticity is still evolving (62-65); however, a number of recent studies indicate that activation of GPER contributes to a rapid increase in hippocampal dendritic spinogenesis and spine density (11,54,57,60,61,66,67).…”

Single-Molecule Imaging Reveals Rapid Estradiol Action on the Surface Movement of AMPA Receptors in Live Neurons

“…The cortical actin network is essential in the organization of neuronal compartments and plays a crucial role in membrane receptor movement ( Schevzov et al, 2012 ), thus we speculated that the cortical actin network may play a pivotal role in the effect of E2 on the receptor dynamics. Previous studies show that E2 induces cytoskeleton assembly mediated by GPER1 receptors via different intracellular signaling pathways, including the Rho-associated protein kinase (ROCK)-cofilin ( Gowrishankar et al, 2012 ; Wang et al, 2019 ) and c-Jun-N-terminal kinase (JNK)-cofilin ( Kim et al, 2019 ) pathways. To determine the possible role of cortical actin in the effects of E2 on glutamate receptors, we treated cells with the actin polymerization inhibitor, latrunculinA (latA; l μM).…”