miR-218: A Stress-Responsive Epigenetic Modifier

Abstract

Understanding the epigenetic role of microRNAs (miRNAs) has been a critical development in the field of neuropsychiatry and in understanding their underlying pathophysiology. Abnormalities in miRNA expression are often seen as key to the pathogenesis of many stress-associated mental disorders, including major depressive disorder (MDD). Recent advances in omics biology have further contributed to this understanding and expanded the role of miRNAs in networking a diverse array of molecular pathways, which are essentially related to the stress adaptivity of a healthy brain. Studies have highlighted the role of many such miRNAs in causing maladaptive changes in the brain’s stress axis. One such miRNA is miR-218, which is debated as a critical candidate for increased stress susceptibility. miR-218 is expressed throughout the brain, notably in the hippocampus and prefrontal cortex (PFC). It is expressed at various levels through life stages, as seen by adolescent and adult animal models. Until now, a minimal number of studies have been conducted on human subjects to understand its role in stress-related abnormalities in brain circuits. However, several studies, including animal and cell-culture models, have been used to understand the impact of miR-218 on stress response and hypothalamic-pituitary-adrenal (HPA) axis function. So far, expression changes in this miRNA have been found to regulate signaling pathways such as glucocorticoid signaling, serotonergic signaling, and glutamatergic signaling. Recently, the developmental role of miR-218 has generated interest, given its increasing expression from adolescence to adulthood and targeting the Netrin-1/DCC signaling pathway. Since miR-218 expression affects neuronal development and plasticity, it is expected that a change in miR-218 expression levels over the course of development may negatively impact the process and make individuals stress-susceptible in adulthood. In this review, we describe the role of miR-218 in stress-induced neuropsychiatric conditions with an emphasis on stress-related disorders.

Dysregulation of microRNAs may contribute to neurosensory impairment in Arctic cod (Boreogadus saida) following CO2 exposure

“…Strikingly, mir-135b showed the highest fold increase (2.51) in fish exposed to low pH. When upregulated, this miRNA helps protect against neuroinflammation and oxidative stress (Schell et al, 2022); the latter stressors have been correlated with hair cell degradation and hearing loss in zebrafish, mice, and humans (Huang et al, 2000;Canlon et al, 2013;Chen et al, 2022). (Lewis et al, 2016, Lewis et al, 2009 Mature miRNA sequences listed with bold nucleotides are non-conserved regions; dashes represent gaps within in the annotated sequence when aligned to the model organism.…”

microRNA-dependent regulation of gene expression in GABAergic interneurons

“…Transient inhibition of miRNA-218 in the dorsal hippocampus in early postnatal life resulted in the disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines in CA1, and increased intrinsic membrane excitability in CA3 pyramidal neurons resulting in a heightened hippocampal network activity and a predisposition to seizures. Previous work has shown that miRNA-218 is implicated in embryonic motor neuron development (Amin et al, 2015(Amin et al, , 2021Thiebes et al, 2015;Reichenstein et al, 2019), in homeostatic plasticity (Rocchi et al, 2019), in stress related responses (Torres-Berrío et al, 2020;Schell et al, 2022;Yoshino et al, 2022), as well as in regulating contextual and spatial memory processes (Lu et al, 2021). Surprisingly, transcriptional profiling revealed that the upregulated genes upon miRNA-218 inhibition were more enriched in INs as compared to pyramidal neurons (Taylor et al, 2022).…”

Inhibitory interneuron classification, function and dysfunction in neural network

“…Transient inhibition of miRNA-218 in the dorsal hippocampus in early postnatal life resulted in the disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines in CA1, and increased intrinsic membrane excitability in CA3 pyramidal neurons resulting in a heightened hippocampal network activity and a predisposition to seizures. Previous work has shown that miRNA-218 is implicated in embryonic motor neuron development (Amin et al, 2015(Amin et al, , 2021Thiebes et al, 2015;Reichenstein et al, 2019), in homeostatic plasticity (Rocchi et al, 2019), in stress related responses (Torres-Berrío et al, 2020;Schell et al, 2022;Yoshino et al, 2022), as well as in regulating contextual and spatial memory processes (Lu et al, 2021). Surprisingly, transcriptional profiling revealed that the upregulated genes upon miRNA-218 inhibition were more enriched in INs as compared to pyramidal neurons (Taylor et al, 2022).…”