Molecular Mechanisms of Oxytocin Signaling at the Synaptic Connection

Bakoš, Ján; Srančíková, Annamária; Havránek, T; Bačová, Zuzana

doi:10.1155/2018/4864107

Cited by 79 publications

(70 citation statements)

References 88 publications

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“…Reduced dendritic spine densities in OTR KO mice. Previous studies suggest that OT signaling in developing brains plays critical roles in development and function of mature synapses 12,13 . Here, we used Golgi staining to label and compare synaptic densities of Otr KO (Otr Venus/Venus ) and heterozygote (Otr Venus/+ ) littermate mice at P21 (N = 3 mice per genotype).…”

Section: Resultsmentioning

confidence: 99%

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Quantitative cellular-resolution map of the oxytocin receptor in postnatally developing mouse brains

et al. 2020

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The oxytocin receptor (OTR) plays critical roles in social behavior development. Despite its significance, brain-wide quantitative understanding of OTR expression remains limited in postnatally developing brains. Here, we develop postnatal 3D template brains to register whole brain images with cellular resolution to systematically quantify OTR cell densities. We utilize fluorescent reporter mice (Otr venus/+) and find that cortical regions show temporally and spatially heterogeneous patterns with transient postnatal OTR expression without cell death. Cortical OTR cells are largely glutamatergic neurons with the exception of cells in layer 6b. Subcortical regions show similar temporal regulation except the hypothalamus and two hypothalamic nuclei display sexually dimorphic OTR expression. Lack of OTR expression correlates with reduced dendritic spine densities in selected cortical regions of developing brains. Lastly, we create a website to visualize our high-resolution imaging data. In summary, our research provides a comprehensive resource for postnatal OTR expression in the mouse brain.

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Section: Resultsmentioning

confidence: 99%

“…This transient OTR expression in the developing cortex is thought to play an important role in facilitating neural circuit maturation 8,9 . For instance, OTR in postnatally developing brains has been implicated in multisensory binding 10 , maturation of GABAergic neurons 11 , and synapse formation and maturation between neurons 12,13 .…”

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confidence: 99%

Quantitative cellular-resolution map of the oxytocin receptor in postnatally developing mouse brains

et al. 2020

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“…Oxytocin signaling pathway has been known to regulate synapse structure, function and neuron connectivity during social interaction 54,55 . Recent studies have found that oxytocin signaling is involved in the differentiation of neuronal progenitor cells 56 , synapse formation 57 and the formation of neural circuits during brain development 58,59 . MAPK signaling pathway 60,61 , estrogen signaling pathway 62,63 and cAMP signaling pathway 64,65 are important for synaptogenesis and synapse pruning and refining.…”

Section: Resultsmentioning

confidence: 99%

Systematic search for schizophrenia pathways sensitive to perturbation by immune activation

Gao

Liang

Ren

et al. 2019

Preprint

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Immune activation has been recently found to play a large part in the development of schizophrenia, but the underlying mechanism remains largely unknown. Here, we report the construction of a high-quality protein interaction network for schizophrenia (SCZ Network) using a "neighborhood walking" approach to searching across human interactome network for disease-related neighborhoods. The spatiotemporal expression pattern of the immune genes in the SCZ Network demonstrates that this disease network is sensitive to the perturbation of immune activation during mid-to late fetal development and adolescence. The immune genes in the network are involved in pathways regulating the formation, structure and function of synapses and neural connections.Using single-cell transcriptome sequencing on the brains of immune-activated mice, we found that immune activation disturbed the SCZ network in the major brain cell types and the dysregulated pathways were also involved in synapse regulation, demonstrating that our "neighborhood walking" approach enables biological discovery in complex disorders. 1 in the selected neighborhoods for removing nodes from the candidate SCZ networks. Using on these optimal cutoffs, we obtained a SCZ Network, which has a seed ratio of 72.3% and contains 3,975 nodes and 92,318 edges, including 869 immune genes (658 known SCZ candidate genes) and 3,106 non-immune genes (2,215 known SCZ candidate genes) ( Fig. 1e, Supplementary Data 4). The high quality SCZ network.The primary purpose of our "neighborhood walking" approach is to extract a high-quality disease network from human interactome by removing false positives of SCZ candidate genes while keeping the true positives and novel candidate genes in the network. Of the 3,437 SCZ candidate genes, 3,265 were mapped on the human interactome ( Fig. 2a). After the "neighborhood walking" process, 2,873 schizophrenia candidate genes and 1,102 novel candidate genes were kept in the SCZ Network (Fig. 1e). In order to verify that the "neighborhood walking" approach has removed false positives and kept true positives, we evaluated the SCZ relevance of the kept genes (genes inside the SCZ Network) and removed genes (genes outside the SCZ Network) using three datasets collected from literature (Supplementary Data 5): (i) dysregulated genes in the brain of schizophrenia patients 39-42 , (ii) variants associated with schizophrenia 43 and (iii) genes with brain-specific expression (Expression Atlas) 44 . Compared to removed genes, the kept genes showed significant enrichment with dysregulated genes in the brains of schizophrenia patients (p = 0.0007 for all kept genes, two-side Fisher's exact tests) ( Fig. 2b, Supplementary Data 5), SCZ-associated variants (p = 5.9827e-98 for all kept genes, p = 7.5082e-07 for kept seeds, p = 0.0183 for kept nonseeds, two-side Fisher's exact tests) ( Fig. 2c, Supplementary Data 5), and brain-specific genes (p = 2.3283e-99 for all kept genes, p = 6.0824e-11 for kept nonseeds, two-side Fisher's exact tests) ( Fig. 2d, Supplementary Dat...

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“…Oxytocin receptor signaling activates MEF2 in a context-dependent manner and thereby induces morphological changes, e.g., neurite retraction (50). Morphological changes in turn determine the synaptic strength and therefore connectivity between oxytocin receptor positive neurons (76). Oxytocin-sensitive neurons are located in brain regions that are part of the salience network (80), which has been shown to be responsive to oxytocin (42) and modulates anxiety-like behavior or the stress response (86, 87).…”

Section: Mef2-driven Mechanisms Affecting Neuronal Connectivitymentioning

confidence: 99%

Anxiolytic and Anxiogenic? How the Transcription Factor MEF2 Might Explain the Manifold Behavioral Effects of Oxytocin

Jurek

Meyer

2020

Front. Endocrinol.

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The neuromodulator oxytocin, since its first synthesis by du Vigneaud in 1953, has mainly been associated with beneficial physiological effects, as well as positive social and emotional behaviors. This overall positive picture of oxytocin as the "love-, cuddle-, or bonding-hormone" has repeatedly been challenged since then. Oxytocin-induced effects that would be perceived as negative by the individual, such as increased anxiety or potentiation of stress-induced ACTH release, as well as the regulation of negative approach-related emotions, such as envy and schadenfreude (gloating) have been described. The general consent is that oxytocin, instead of acting unidirectional, induces changes in the salience network to shift the emphasis of emotional contexts, and therefore can, e.g., produce both anxiolytic as well as anxiogenic behavioral outcomes. However, the underlying mechanisms leading to alterations in the salience network are still unclear. With the aim to understand the manifold effects of oxytocin on a cellular/molecular level, a set of oxytocin receptor-coupled signaling cascades and downstream effectors regulating transcription and translation has been identified. Those oxytocin-driven effectors, such as MEF2 and CREB, are known modulators of the neuronal and glial cytoarchitecture. We hypothesize that, by determining cellular morphology and connectivity, MEF2 is one of the key factors that might contribute to the diverse behavioral effects of oxytocin.

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Molecular Mechanisms of Oxytocin Signaling at the Synaptic Connection

Cited by 79 publications

References 88 publications

Quantitative cellular-resolution map of the oxytocin receptor in postnatally developing mouse brains

Quantitative cellular-resolution map of the oxytocin receptor in postnatally developing mouse brains

Systematic search for schizophrenia pathways sensitive to perturbation by immune activation

Anxiolytic and Anxiogenic? How the Transcription Factor MEF2 Might Explain the Manifold Behavioral Effects of Oxytocin

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