The review, led by Nuo Yang and colleagues at Tianjin Medical University General Hospital together with Feixiang Li of Beijing Chao-Yang Hospital at Capital Medical University, synthesizes evidence on how three estrogen receptor subtypes—estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and the G protein-coupled estrogen receptor 1 (GPER1)—are expressed across the lifespan in the brain regions most critical for cognition, including the hippocampus and the prefrontal cortex. The central argument is striking: these receptors do not simply sit still. Their expression shifts dramatically across developmental stages, and those shifts create windows of vulnerability during which anesthetic exposure can derail the delicate hormonal signaling that neurons depend on to grow, connect, and communicate.

To understand why this matters, it helps to appreciate what estrogen receptors actually do in the brain. Far from being limited to reproductive functions, they act as master regulators of neurogenesis, synaptic plasticity, and cell survival. The classical nuclear receptors, ERα and ERβ, function as ligand-activated transcription factors: when bound by estrogen, they migrate to the genome and attach to specific DNA sequences called estrogen response elements, dialing up or down the expression of genes involved in neuronal growth and maintenance. They can also act through other transcription factors such as AP-1 and SP-1, giving them flexible control over gene programs. ERα and ERβ differ in their activation domains—the AF-1 and AF-2 regions—and this structural divergence means they often regulate different gene sets, sometimes in opposing directions. Meanwhile, GPER1 operates at the cell membrane, triggering rapid signaling cascades through G proteins, including the stimulatory Gαs, inhibitory Gαi, and the Gβγ subunits, which in turn activate pathways such as PI3K/Akt, MAPK/ERK, and other kinase networks within minutes rather than hours.

The review emphasizes that the balance among these receptor subtypes changes with age in a region-specific manner. During the perinatal period, when the brain is laying down its foundational circuits, estrogen signaling helps orchestrate the birth of new neurons and the formation of synapses. Markers of neurogenesis, such as doublecortin (DCX), and structural components of synapses, such as postsynaptic density protein 95 (PSD-95) and synaptophysin (SYP), are all influenced by estrogen receptor activity. In the hippocampus—a seahorse-shaped structure essential for forming new memories—and in the prefrontal cortex, which governs executive function and working memory, the relative abundance of ERα, ERβ, and GPER1 shifts as the brain matures, remodels during adolescence, and eventually declines in old age. This dynamic ebb and flow forms what the authors describe as a molecular basis for the regulation of cognitive function across the entire lifespan.

Against this backdrop, the review examines how general anesthetics can interfere with endogenous estrogen signaling. Many commonly used anesthetic agents act on gamma-aminobutyric acid type A receptors (GABAAR) and NMDA receptors, producing the sedation and immobility that surgery requires. But accumulating evidence indicates that anesthetic exposure can also disrupt estrogen receptor pathways in the brain, and this disruption appears to converge on several damaging mechanisms. The review identifies four key processes: synaptic injury, neuroinflammation, mitochondrial stress, and Tau pathology. Each of these can be modulated by estrogen receptor signaling, which means that the state of a patient’s estrogen system at the time of anesthesia may shape how much harm the drugs do.

Of the three receptor subtypes, ERα-mediated pathways emerge as the most established mechanistic targets in anesthetic neurotoxicity. Studies summarized in the review suggest that when anesthetics perturb ERα signaling, the downstream consequences ripple through the PI3K/Akt pathway, which normally promotes cell survival, and through CREB-dependent gene expression, which supports long-term potentiation (LTP)—the cellular substrate of learning and memory. Disruption of these pathways can weaken synapses in the CA1 region of the hippocampus and impair memory consolidation. ERα also interacts with neurotrophic factors such as brain-derived neurotrophic factor (BDNF), which neurons rely on to maintain their connections. When this support system falters, synaptic proteins like PSD-95 and synaptophysin decline, and the structural integrity of neural circuits erodes.

The other two subtypes present a more complicated picture. ERβ has often been described as neuroprotective, and evidence suggests it can counteract inflammation by modulating nuclear factor kappa B (NF-κB) signaling, a central hub of the inflammatory response. It may also influence the clearance of amyloid beta (Aβ), the peptide that accumulates in Alzheimer’s disease, partly through enzymes such as neprilysin (NEP). GPER1, the newest and least well-characterized member of the family, activates fast signaling through EGFR transactivation and other membrane-proximal mechanisms, but the review is candid that its role in anesthetic-induced cognitive dysfunction remains under-validated. The authors note that while ERα pathways are the best supported, ERβ and GPER1 require further investigation before they can be considered reliable therapeutic targets.

One of the review’s most consequential themes is the role of sex and age in determining vulnerability. Perioperative neurocognitive disorders (PNDs)—an umbrella term covering the delirium and longer-lasting cognitive decline that can follow surgery—do not strike uniformly. The developing brain, with its immature and still-shifting estrogen receptor landscape, appears especially susceptible, as does the aging brain, where estrogen signaling homeostasis is already fragile. Sex differences add another layer of complexity: ovarian estrogen production, and its loss after menopause or ovariectomy, changes the hormonal milieu in ways that alter how the brain responds to anesthetic challenge. Clinical studies, including trials such as the General Anesthesia compared with Spinal anesthesia (GAS) study, have attempted to untangle the real-world consequences of early anesthetic exposure, though the review suggests that laboratory findings on receptor mechanisms have not yet been fully translated into clinical prevention strategies.

The mechanistic detail extends to pathology usually associated with neurodegenerative disease. The review describes how anesthetic exposure can promote Tau pathology, the tangle-forming protein hallmark of Alzheimer’s disease, potentially through kinases such as Tau tubulin kinase 1 (TTBK1), and how mitochondrial stress and calcium dysregulation feed into a self-reinforcing cycle of damage. Inflammatory signaling molecules, including high mobility group box 1 (HMGB1), link the synaptic and immune dimensions of anesthetic neurotoxicity. Estrogen receptors sit at the crossroads of all these processes: when their signaling is intact, they buffer the brain against stress; when anesthetics disrupt them, the buffers fail.

Looking forward, the authors argue that the field needs to move beyond broad correlations and toward precision. They propose integrating cell-specific gene editing—using tools delivered by adeno-associated viruses (AAV)—with brain organoids, the lab-grown miniature brain models that can recapitulate human developmental processes, and with clinical cohort investigations that track real patients over time. Such approaches could finally resolve which receptor subtype matters most at which age, in which sex, and in which brain region, paving the way for targeted interventions that protect the estrogen signaling system during surgery. For now, the review’s message is a sobering but hopeful one: the hormones that build the brain may also be the key to defending it from one of modern medicine’s most routine interventions.

Subject of Research: The role of dynamic estrogen receptor subtype expression in brain development and anesthetic-induced cognitive dysfunction

Article Title: Dynamic expression of estrogen receptor subtypes during brain development and their mechanistic roles in anesthetic-induced cognitive dysfunction: a review

Article References: Yang, N., Li, F., Liu, Y., Yang, Y., & Yu, Y. (2026). Dynamic expression of estrogen receptor subtypes during brain development and their mechanistic roles in anesthetic-induced cognitive dysfunction: a review. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00994-7

Image Credits: AI Generated

DOI: 10.1186/s13293-026-00994-7

Keywords: estrogen receptor, anesthetic neurotoxicity, perioperative neurocognitive disorders, hippocampus, prefrontal cortex, synaptic plasticity, neuroinflammation, ER alpha, ER beta, GPER1, brain development, sex differences

Researchers at Weill Cornell Medicine, led by Teresa A. Milner and Michael J. Glass, set out to dissect why blood pressure control goes awry when estrogen declines. Studying hypertension in female animals has long been hampered by a modeling problem: surgically removing the ovaries produces an abrupt hormonal cliff that does not resemble natural menopause, while simply aging rodents produces a partial hormone decline mixed with the confounding effects of chronological aging. To get around this, the team used a chemical called 4-vinylcyclohexene diepoxide, or VCD, which selectively destroys ovarian follicles and produces a staged hormonal decline. In this model, mice first pass through a phase resembling perimenopause, with irregular estrogen fluctuations, and then reach a phase termed post-accelerated ovarian failure, in which estrogen is undetectable, progesterone is reduced, and pituitary hormones are elevated — a hormonal profile closely mirroring human postmenopause.

The team then induced hypertension using a slow-pressor regimen of angiotensin II, delivered by osmotic minipump over fourteen days at a dose that gradually raises blood pressure. Systolic blood pressure was tracked by tail-cuff plethysmography. Both post-menopausal model females and age-matched males developed comparable hypertension in response to the hormone. But when the researchers peered into the paraventricular nucleus of the hypothalamus — a command center housing neurons that project to the spinal cord and drive the sympathetic nervous system — they found that the two sexes had arrived at high blood pressure by fundamentally different neural routes.

Using whole-cell voltage-clamp electrophysiology on brain slices, the researchers recorded from spinally-projecting PVN neurons that had been retrogradely labeled with a fluorescent tracer. In hypertensive post-menopausal females, the surprise was what did not change: NMDA receptor-mediated currents were unaltered, in contrast to previous findings in earlier stages of ovarian decline where NMDA signaling dominates. Instead, AMPA receptor currents — fast excitatory signaling mediated by the GluA1 subunit — were selectively elevated. Blocking calcium-permeable, GluA2-lacking AMPA receptors with the spider-toxin-derived antagonist Naspm abolished this difference, pinpointing the AMPA receptor subtype responsible. In males, by contrast, hypertension recruited both AMPA and NMDA currents, consistent with earlier work, and the relative amplification of AMPA signaling was even greater than in females.

The molecular machinery behind these currents proved equally revealing. GluA1-containing AMPA receptors are tethered at the neuronal plasma membrane by AKAP150, a scaffolding protein that anchors protein kinase A and other effectors. When the researchers disrupted the AKAP150–PKA interface with the cell-permeable peptide st-Ht31, the heightened AMPA currents in hypertensive animals of both sexes collapsed back toward baseline — evidence that a shared scaffold supports the hypertensive response in both groups. Genetically silencing GluA1 in the PVN with an adeno-associated virus expressing a short hairpin RNA blunted the blood pressure rise in post-menopausal females, confirming that this receptor is not merely a correlate of hypertension but a functional contributor.

Beyond the electrophysiology, the team deployed electron microscopy with immunogold labeling to map exactly where AKAP150 sits within dendrites. In small, distal dendrites of PVN neurons — the compartments that receive dense excitatory input — hypertensive post-menopausal females showed a striking increase in AKAP150 particles parked directly on the plasma membrane. Males showed no such redistribution. At the gene level, the picture inverted: hypertensive males, but not females, showed increased expression of Prkaca, the gene encoding the catalytic subunit of PKA. Consistent with this, mutating the Ser845 phosphorylation site on GluA1 — the residue PKA modifies to control receptor trafficking to the membrane — slightly but significantly reduced hypertension in male mice while leaving the female response untouched.

Here the story took an unexpected turn toward estrogen biology. Estrogen can act not only through classic nuclear receptors but through GPER1, a G-protein-coupled receptor that resides at the plasma membrane and is known to associate with the AKAP150 complex. Because estrogen is essentially absent in post-menopausal model females, the researchers hypothesized that GPER1, though unliganded, might still be positioned to modulate AMPA signaling if artificially activated. When they applied G-1, a selective GPER1 agonist, to slices from hypertensive post-menopausal females, the elevated AMPA currents in PVN projection neurons were significantly suppressed.

The whole-animal results were even more dramatic. Cyclically administering G-1 alongside the fourteen-day angiotensin II infusion completely prevented the rise in systolic blood pressure in post-menopausal females — while having no effect whatsoever in hypertensive males. GPER1 stimulation also increased expression of Akap5, the gene encoding AKAP150, in the PVN of females regardless of whether they were hypertensive, suggesting the receptor reshapes its own signaling platform. Notably, activating estrogen receptor beta with the agonists DPN or ERB-041 neither reduced AMPA currents nor lowered blood pressure in these animals, indicating that the protective effect at this late stage of ovarian failure is GPER1-specific and that different estrogen receptors govern different phases of the menopausal transition.

Taken together, the study sketches a striking biological divergence: two sexes develop the same measurable hypertension through a common hypothalamic hub, yet one relies on a classical PKA–Ser845 pathway while the other depends on an unconventional AMPA–AKAP150–GPER1 signaling axis that can be pharmacologically disengaged. The findings help explain why hypertension vulnerability in women shifts across the life course, from a protected state during reproductive years to heightened risk after menopause, and why earlier stages of ovarian decline appear governed by entirely different receptor systems. They also carry translational weight: a hypofunctional variant of the human GPER1 gene has been linked to elevated blood pressure in women specifically. If the mouse findings hold in humans, targeting GPER1 could one day offer a precision approach to treating the hypertension that shadows so many women after menopause — one that respects the fact that, at the level of the hypothalamus, male and female brains are solving the same problem with different molecular tools.