Insights into rapid modulation of neuroplasticity by brain estrogens

Abstract

Converging evidence from cellular, electrophysiological, anatomic, and behavioral studies suggests that the remodeling of synapse structure and function is a critical component of cognition. This modulation of neuroplasticity can be achieved through the actions of numerous extracellular signals. Moreover, it is thought that it is the integration of different extracellular signals regulation of neuroplasticity that greatly influences cognitive function. One group of signals that exerts powerful effects on multiple neurologic processes is estrogens. Classically, estrogens have been described to exert their effects over a period of hours to days. However, there is now increasing evidence that estrogens can rapidly influence multiple behaviors, including those that require forebrain neural circuitry. Moreover, these effects are found in both sexes. Critically, it is now emerging that the modulation of cognition by rapid estrogenic signaling is achieved by activation of specific signaling cascades and regulation of synapse structure and function, cumulating in the rewiring of neural circuits. The importance of understanding the rapid effects of estrogens on forebrain function and circuitry is further emphasized as investigations continue to consider the potential of estrogenic-based therapies for neuropathologies. This review focuses on how estrogens can rapidly influence cognition and the emerging mechanisms that underlie these effects. We discuss the potential sources and the biosynthesis of estrogens within the brain and the consequences of rapid estrogenic-signaling on the remodeling of neural circuits. Furthermore, we argue that estrogens act via distinct signaling pathways to modulate synapse structure and function in a manner that may vary with cell type, developmental stage, and sex. Finally, we present a model in which the coordination of rapid estrogenic-signaling and activity-dependent stimuli can result in long-lasting changes in neural circuits, contributing to cognition, with potential relevance for the development of novel estrogenic-based therapies for neurodevelopmental or neurodegenerative disorders.

Fig. 1.

Examining neural circuits by two-photon imaging of transgenic mice expressing GFP. (A) Two-photon image of cortical pyramidal neurons in coronal sections of GFP M-line mice; a subset of layer 5 cells express GFP. The main (apical) dendrite of these cells is branched and projects to layer 1; dendritic spines are located along the dendrite. (B) High magnification image of dendrite, dendritic spines, and axon imaged by intravital two-photon microscopy. Dendritic spines protrude from dendrites, allowing neurons to make synaptic connections. Note that the axon is thinner than dendrites and does not have spines. Image demonstrates dendritic spines synapsing with an axon. (C) Examples of dendritic spine plasticity, imaged in vivo: novel spines can form (formation), whereas existing spines can change shape and size (retract, grow, or become longer); spines can also be eliminated. Dendritic spines change morphology in response to numerous extracellular stimuli; this can be a consequence of synaptic activity or neuromodulatory stimuli. Intravital two-photon images were acquired with the aid and expertise of Dr. Jack Waters, Northwestern University. (D) Schematic of cortical circuitry rewiring. The strengthening or weakening of existing synaptic connections and the addition or elimination of synaptic connections allows for the bidirectional rewiring of cortical circuits.

Fig. 2.

General schematic of the localization of ERs and signaling cascade engaged during rapid estrogenic signaling. All 3 forms of ERs (ERα, ERβ, and GPER) have been localized to pre- and postsynaptic structures where they are thought to associate with lipid-rich structures and spine organelle, including the plasma membrane spine apparatus and endoplasmic reticulum. Emerging evidence suggests that rapidly synthesized estrogens within the brain, mediated by synaptically located aromatase, is the source of rapid estrogenic signaling in the brain. Synthesis and “release” of estrogens onto postsynaptic cells results in the activation of ERs and the rapid transactivation of other membrane receptors or (direct) association with signaling molecules. The functional coupling of ERs via these mechanisms thus allows activation of second messenger systems and multiple intracellular cascades that ultimately lead to the regulation of the cytoskeleton, trafficking of proteins, and even the rapid synthesis of proteins, resulting in the remodeling of synapse structure and function.

Fig. 3.

Dendritic spines and the cytoskeleton. Immunofluorescence staining with phalloidin, a marker of endogenous F-actin in cortical neurons, reveals enrichment of actin in dendrites and dendritic spines. Schematic drawing of how extracellular signals can act via specific receptors and act via small GTPases to regulate actin dynamics and/or receptor trafficking. The dynamic actin cytoskeleton confers much of the structure of the dendritic spines, and alterations in synaptic expression of glutamate receptors (e.g., AMPA receptors) are thought to play a major role in modulating synaptic function.

Fig. 4.

Estrogen-induced “two-step wiring plasticity” in cortical neurons. This form of “wiring” plasticity can be divided into three distinct phases. Phase 1: treatment with 17 β-estradiol induces the formation of novel spines, which form connections with pre-synaptic partners within 30 minutes. Concurrently GluA1-containing AMPA receptors are removed from existing spines, and GluN1-containing NMDA receptors are trafficked into nascent spines. Overall, this results in an increased number of connections between cells and a reduction in AMPA receptor transmission. Phase 2A: effect on dendritic spines and glutamate receptors is transient: 60 minutes after treatment, estradiol-induced spines are preferentially eliminated and GluA1-containing AMPA receptors and GluN1-containing NMDA receptors return to control levels. Therefore, the number of connections returns to control levels, and AMPA receptor-transmission returns to normal. Or, Phase 2B: addition of a second synaptic activity-like stimulus results in the stabilization of estradiol-induced spines and a trafficking of GluA1-containing AMPA receptors back into existing and nascent synapses as observed immediately after the completion of treatment or 24 hours post-treatment. This combined treatment may lead to long-lasting (24 hour) increase in connectivity and increase synaptic communication.