Social defeat stress in adult mice causes alterations in gene expression, alternative splicing, and the epigenetic landscape of H3K4me3 in the prefrontal cortex: An impact of early-life stress

Reshetnikov, Vasiliy V.; Kisaretova, Polina E.; Ershov, Nikita I.; Меркулова, Т. И.; Bondar, Natalia P.

doi:10.1016/j.pnpbp.2020.110068

Cited by 26 publications

(21 citation statements)

References 93 publications

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“…Given that HOMER1a is known to be a dominant negative isoform, it can be assumed that the decrease in its amount enhances HOMER1b,c mediated signaling. The similar decrease in Homer1 expression in the prefrontal cortex of adult male mice exposed to chronic social defeat stress and explained mainly by downregulation of HOMER1a expression was noted in our work [67].…”

Section: Participation Of Homer1 In Adaptation To Chronic Stresssupporting

confidence: 90%

“…The data presented so far indicate that acute stress mostly increases HOMER1a expression in various regions of the brain, whereas chronic stress most often upregu lates isoforms HOMER1b and/or HOMER1c in the hip pocampus. It is noteworthy that these changes in the HOMER1a/HOMER1b/HOMER1c ratio in the hip pocampus or prefrontal cortex can determine resistance or susceptibility to stress [65,67]. These data are in good agreement with the previous studies demonstrating that the induction of Homer1a in the cortical structures allows better adaptation to stressful conditions [88] and has a pronounced antidepressant effect [22, 89 91].…”

Section: Genetic Variants Of Homer1 Associated With the Development Of Depression And Other Mental Disorderssupporting

confidence: 88%

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The Role of Stress-Induced Changes of Homer1 Expression in Stress Susceptibility

Reshetnikov

Bondar

2021

Biochemistry Moscow

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Stress negatively affects processes of synaptic plasticity and is a major risk factor of various psychopathologies such as depression and anxiety. HOMER1 is an important component of the postsynaptic density: constitutively expressed long isoforms HOMER1b and HOMER1c bind to group I metabotropic glutamate receptors MGLUR1 (GRM1) and MGLUR5 and to other effector proteins, thereby forming a postsynaptic protein scaffold. Activation of the GLUR1–HOMER1b,c and/or GLUR5–HOMER1b,c complex regulates activity of the NMDA and AMPA receptors and Ca2+ homeostasis, thus modulating various types of synaptic plasticity. Dominant negative transcript Homer1a is formed as a result of activity-induced alternative termination of transcription. Expression of this truncated isoform in response to neuronal activation impairs interactions of HOMER1b,c with adaptor proteins, triggers ligand-independent signal transduction through MGLUR1 and/or MGLUR5, leads to suppression of the AMPA- and NMDA-mediated signal transmission, and thereby launches remodeling of the postsynaptic protein scaffold and inhibits long-term potentiation. The studies on animal models confirm that the HOMER1a-dependent remodeling most likely plays an important part in the stress susceptibility, whereas HOMER1a itself can be regarded as a neuroprotector. In this review article, we consider the effects of different stressors in various animal models on HOMER1 expression as well as impact of different HOMER1 variants on human behavior as well as structural and functional characteristics of the brain.

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Section: Participation Of Homer1 In Adaptation To Chronic Stresssupporting

confidence: 90%

Section: Genetic Variants Of Homer1 Associated With the Development Of Depression And Other Mental Disorderssupporting

confidence: 88%

The Role of Stress-Induced Changes of Homer1 Expression in Stress Susceptibility

Reshetnikov

Bondar

2021

Biochemistry Moscow

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“…Four mice from each group were chosen for RNA-seq. RNA-seq libraries of the murine hippocampus were prepared in accordance with the standard New England Biolabs protocol used earlier in our lab 80 , 81 . Briefly, polyA-tailed mRNAs were purified from 1 µg of total RNA using the NEBNext Poly(A) mRNA Magnetic Isolation Module.…”

Section: Methodsmentioning

confidence: 99%

Genes associated with cognitive performance in the Morris water maze: an RNA-seq study

Reshetnikov

Kisaretova

Ershov

et al. 2020

Sci Rep

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Learning and memory are among higher-order cognitive functions that are based on numerous molecular processes including changes in the expression of genes. To identify genes associated with learning and memory formation, here, we used the RNA-seq (high-throughput mRNA sequencing) technology to compare hippocampal transcriptomes between mice with high and low Morris water maze (MWM) cognitive performance. We identified 88 differentially expressed genes (DEGs) and 24 differentially alternatively spliced transcripts between the high- and low-MWM-performance mice. Although the sets of DEGs and differentially alternatively spliced transcripts did not overlap, both were found to be enriched with genes related to the same type of biological processes: trans-synaptic signaling, cognition, and glutamatergic transmission. These findings were supported by the results of weighted-gene co-expression network analysis (WGCNA) revealing the enrichment of MWM-cognitive-performance-correlating gene modules with very similar Gene Ontology terms. High-MWM-performance mice manifested mostly higher expression of the genes associated with glutamatergic transmission and long-term potentiation implementation, which are processes necessary for memory acquisition and consolidation. In this set, there were genes participating in the regulation of trans-synaptic signaling, primarily AMPA receptor signaling (Nrn1, Nptx1, Homer3, Prkce, Napa, Camk2b, Syt7, and Nrgn) and calcium turnover (Hpca, Caln1, Orai2, Cpne4, and Cpne9). In high-MWM-performance mice, we also demonstrated significant upregulation of the “flip” splice variant of Gria1 and Gria2 transcripts encoding subunits of AMPA receptor. Altogether, our data helped to identify specific genes in the hippocampus that are associated with learning and long-term memory. We hypothesized that the differences in MWM cognitive performance between the mouse groups are linked with increased long-term potentiation, which is mainly mediated by increased glutamatergic transmission, primarily AMPA receptor signaling.

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“…Significant alterations in H3K9me2 levels, reversed by chronic antidepressant treatment, have also been found in the nucleus accumbens of mice exposed to chronic social defeat or chronic social isolation [97]. Moreover, mice with a history of early-life stress showed enhanced susceptibility to social defeat stress in adulthood and had genome-wide alterations in H3K4me3 levels in the prefrontal cortex [98]. Changes in H3K4me3 levels at synapsin genes have also been found in postmortem brain samples from individuals with major depression and bipolar disorder [99].…”

Section: Cbd and Histone Modificationsmentioning

confidence: 97%

Cannabidiol as a Potential Treatment for Anxiety and Mood Disorders: Molecular Targets and Epigenetic Insights from Preclinical Research

Melas

Scherma

Fratta

et al. 2021

IJMS

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Cannabidiol (CBD) is the most abundant non-psychoactive component of cannabis; it displays a very low affinity for cannabinoid receptors, facilitates endocannabinoid signaling by inhibiting the hydrolysis of anandamide, and stimulates both transient receptor potential vanilloid 1 and 2 and serotonin type 1A receptors. Since CBD interacts with a wide variety of molecular targets in the brain, its therapeutic potential has been investigated in a number of neuropsychiatric diseases, including anxiety and mood disorders. Specifically, CBD has received growing attention due to its anxiolytic and antidepressant properties. As a consequence, and given its safety profile, CBD is considered a promising new agent in the treatment of anxiety and mood disorders. However, the exact molecular mechanism of action of CBD still remains unknown. In the present preclinical review, we provide a summary of animal-based studies that support the use of CBD as an anxiolytic- and antidepressant-like compound. Next, we describe neuropharmacological evidence that links the molecular pharmacology of CBD to its behavioral effects. Finally, by taking into consideration the effects of CBD on DNA methylation, histone modifications, and microRNAs, we elaborate on the putative role of epigenetic mechanisms in mediating CBD’s therapeutic outcomes.

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Social defeat stress in adult mice causes alterations in gene expression, alternative splicing, and the epigenetic landscape of H3K4me3 in the prefrontal cortex: An impact of early-life stress

Cited by 26 publications

References 93 publications

The Role of Stress-Induced Changes of Homer1 Expression in Stress Susceptibility

The Role of Stress-Induced Changes of Homer1 Expression in Stress Susceptibility

Genes associated with cognitive performance in the Morris water maze: an RNA-seq study

Cannabidiol as a Potential Treatment for Anxiety and Mood Disorders: Molecular Targets and Epigenetic Insights from Preclinical Research

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