What Role Might the G Protein-Coupled Estrogen Receptor 1 Have in Treating Schizophrenia?

As G protein-coupled estrogen receptor 1 (GPER), which regulates non-genomic estrogen functions, aids in social cognition, and learning and memory, schizophrenia’s complications include cognitive deficit and social impairment. Apoptotic mechanisms and immunoinflammatory alternations are also a part of the pathophysiology of the disease. The investigators decided to evaluate what GPER’s role could be in schizophrenia treatment in a literature review that was published in the journal, Schizophrenia Bulletin Open.

The investigators examined literature reviews and observational and experimental studies of animals and human participants published in English through July 2020 in the PubMed/MEDLINE database that involved schizophrenia, GPER1 protein, estrogen receptors (ER), SERMS, GPER1 agonism, behavioral symptoms, and brain inflammation.

They provided a summary of the literature data and commentary on the significance of GPER, its intracellular mechanisms, and whether GPER-targeted treatment could be effective for patients with schizophrenia.

Studies indicated that GPER amplifies or diminishes nuclear ERs, and in the dorsal striatum is exclusively found at extranuclear sites, along with ERα and Erβ, and that GPER polymorphisms associated with schizophrenia are still unknown, the researchers said. GPER may also control microglial reactivity.

Sex and age influence the expression and function of GPER, they also found in their review of studies that involved mice and hamsters.  For example, in the hypothalamus of adult hamsters, gene expression of GPER is higher in adult females than in adult males, while the gene expression is higher in the thalamus of the adult male than in the adult female, and researchers have seen GPER agonism have varying protective effects in rodents based on the animals’ ages.

“Such observations suggest that the interaction among estrogen receptors needs to be studied in animal models of schizophrenia, both male and female and of different ages,” the researchers who conducted the literature review said. “GPER and its interaction with other ERs throughout the estrous cycle of females also needs to be investigated in order to understand the neurobiological mechanisms underlying perimenstrual susceptibility to increased levels of psychosis.”

GPER’s position in the synapse indicates that it may be involved in activity-dependent synaptic plasticity that occurs during memory formation in the hippocampus.

GPER can also be found in basal forebrain cholinergic neurons, and studies have suggested that using a GPER agonist, G-1, leads to increased spatial memory in ovariectomized rats, while the GPER antagonist, G-15, has impaired working and spatial memory in ovariectomized rats. Female rats’ social learning skills rapidly improved with GPER-agonist G-1.

GPER also may have a role in anxiety and depression, though its impact is not yet clear. While GPER-deficient rats showed increased anxiety, timing and dose of the G-1 agonist can increase or decrease anxiety-like behavior in rats, and a study that involved humans as subjects indicated that GPER serum might be a biomarker for major depressive disorder (MDD). In that study, higher levels of GPER and anxiety symptoms were both found in drug-naïve patients with MDD and there was a positive correlation between GPER1 levels and depression scores.

GPER regulates intracellular Ca²⁺ and the activation of matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, which may be involved in the remodeling of neural circuits following neural activity and brain damage. GPER’s activation in neurons tends to induce pro-survival pathways, such as phosphatidylinositol 3-kinase (PI3K). The disruption of PI3K is implicated in the pathogenesis of schizophrenia.

“To date, there is no direct evidence that the pharmacological or genetic modulation of GPER would be beneficial in the treatment of schizophrenia, but this remains an interesting possibility,” the researchers said.

“As previously mentioned, GPER modulates several intracellular mechanisms that are compromised in schizophrenia. There is compelling evidence of an aberrant pro-inflammatory microglial phenotype in the schizophrenia brain, which may explain the synaptic pruning disruption seen in adolescence and the progressive neurodegenerative changes that occur over time. Based on the intracellular mechanisms modulated by GPER and their relevance for schizophrenia, we speculate that GPER could become a useful pharmacological target for new immunomodulatory and potentially sex-specific treatment strategies.”

Reference

Macêdo DS, Olivier Sanders LL, das Candeias R, et al. G protein-coupled estrogen receptor 1 (GPER) as a novel target for schizophrenia drug treatment [published online November 11, 2020]. Schizophr Bull Open. doi: 10.1093/schizbullopen/sgaa062