Human microRNAs miR-22, miR-138-2, miR-148a, and miR-488 Are Associated with Panic Disorder and Regulate Several Anxiety Candidate Genes and Related Pathways

Muiños‐Gimeno, Margarita; Espinosa‐Parrilla, Yolanda; Guidi, Monia; Kagerbauer, Birgit; Sipilä, Tessa; Maron, Eduard; Pettai, Kristi; Kananen, Laura; Navinés, Ricard; Martín‐Santos, Rocío; Gratacòs, Mónica; Metspalu, Andres; Hovatta, Iiris; Estivill, Xavier

doi:10.1016/j.biopsych.2010.10.010

Cited by 161 publications

(120 citation statements)

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“…Clinical association studies have identified more than 10 candidate genes for PTSD (5,42), whereas the CCKR-2 gene has been repeatedly associated to panic disorder, another major form of anxiety disorders (10). Moreover, polymorphisms in microRNAs that are associated to panic disorder are also functionally related to the CCKergic system (43). It should be noted that panic disorder and PTSD are basically two types of anxiety disorders.…”

Section: Discussionmentioning

confidence: 99%

Temporal association of elevated cholecystokininergic tone and adolescent trauma is critical for posttraumatic stress disorder-like behavior in adult mice

Joseph

Tang

Mamiya

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Adolescent trauma (AT) is a common risk factor for adult-onset posttraumatic stress disorder (PTSD). However, the vulnerability to AT among different individuals varies dramatically, indicating that other cofactors are important. Despite extensive studies, the identification of those cofactors has had little success. Here, we found that after subjected to traumatic stress at postnatal day 25 (P25), a stage that is comparable to the human adolescent period, inducible/ reversible forebrain-specific cholecystokinin receptor-2 transgenic (IF-CCKR-2 tg) mice exhibited a significantly higher level of PTSD-like behavior at a later life (adult) stage compared with their wild-type littermates. Moreover, in these traumatized IF-CCKR-2 tg mice, both the glucocorticoid negative feedback inhibition and spatial learning and memory were impaired. Interestingly, if the CCKR-2 transgene was specifically suppressed during the time of AT exposure, these observations were largely diminished, indicating that a temporal association of the elevated CCKergic tone and AT is pathogenically critical. Treatment of traumatized IF-CCKR-2 tg mice with fluoxetine, a selective serotonin reuptake inhibitor, for a period of 4 wk significantly attenuated the PTSD-like behavior and the impaired glucocorticoid negative feedback inhibition, but not the memory deficit, implying that the memory deficit is an independent post-AT clinical entity and not a consequence of PTSD. Taken together, these results reveal a dynamic role of the CCKergic system in the development of post-AT psychopathologies and suggest that a timely antagonism of CCKR-2 activity during AT exposure is a potential preventive strategy for post-AT psychopathologies including PTSD and cognitive dysfunction.anxiety disorder | animals model | face validity | constructive validity | predictive validity P osttraumatic stress disorder (PTSD), as a predominant form of anxiety disorders, affects 7.8% of people of ages between 15 and 54 y in the United State (1). This prevalence goes up to 32-36% in people who have a history of trauma (2). Particularly, over half of the victims who experienced a preadult trauma such as childhood physical or sexual abuse eventually develop PTSD (3). Given that children, especially early adolescents, have a higher possibility of exposure to traumatic attacks (4), adolescent trauma (AT) is an important risk factor for PTSD. However, the vulnerability among different individuals to AT is different, and this variability may at least partially be attributed to genetic variations (5). Another important factor is pretrauma stress (6). Stress may dysregulate various neurotransmitter systems in the brain, among which the CCKergic system, including cholecystokinin (CCK) peptides and their receptors, is of a significant importance, based on its dynamic regulation in response to stress (7,8). Actually, the CCKergic system has long been recognized as an anxiogenic factor (7), and CCK peptides were commonly used to induce anxiety in volunteers (9, 10). CCK peptides and CCK re...

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Section: Discussionmentioning

confidence: 99%

Temporal association of elevated cholecystokininergic tone and adolescent trauma is critical for posttraumatic stress disorder-like behavior in adult mice

Joseph

Tang

Mamiya

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In an attempt of identifying genetic factors related to anxiety, we divided our strategy into the study of genetic variation in regulatory regions of candidate genes for anxiety disorders and the genetic study of miRNA genes "per se". As described later, even though major risk alleles have not been found, results on these studies indicate that genetic variation affecting miRNA-mediated regulation may be underlying a range of anxiety related phenotypes, being the first time that miRNAs are involved in the pathophysiology of human anxiety disorders (Muiños-Gimeno et al, 2009;2011). Table 1 shows a list of all miRNAs that have been involved in anxiety disorders.…”

Section: Micrornas and Anxiety Disordermentioning

confidence: 99%

“…Even though poorly considered until now, association studies using SNPs in miRNA genomic regions might help to evaluate the involvement of miRNAs genes in disease. In this regard, a panel of SNPs covering miRNA regions suitable for association studies was designed, constructed and used for the study of panic disorder 2011). Prior to the design of the SNP panel, the first step consisted in the analysis of the genomic distribution and genetic variation of all at that moment known miRNAs-containing regions.…”

Section: Association Studies Of Mirna Genes With Anxiety Disordermentioning

confidence: 99%

“…We will explore the hypothesis that changes in miRNA-mediated regulation, originated from changes in the miRNAs themselves or on their target sites, may alter the dosage of proteins involved in fundamental pathways for brain function, affecting the precise homeostasis of the central nervous system and contributing to the development of anxiety disorders. The chapter will go through recent research results that, by a combination of association analyses and functional approaches, involves particular miRNAs and several candidate genes in the susceptibility for anxiety disorders and indicates that polymorphisms affecting miRNA-mediated regulation may be determinant of a range of human traits related to anxiety (Muiños-Gimeno et al, 2009;2011).…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-Mediated Regulation and the Genetic Susceptibility to Anxiety Disorders

Espinosa‐Parrilla¹,

Muiños‐Gimeno²

2011

Anxiety Disorders

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“…Cite this article as Cold Spring Harb Perspect Med 2013;3:a012047 number of miRNAs can bind directly to the 3 0 -UTR of Bdnf (Mellios et al 2008;Friedman et al 2009a;Muinos-Gimeno et al 2011), the relevance of this epigenetic mechanism for the in vivo regulation of BDNF levels remains to be determined. However, miRNAs may impact cocaine-induced BDNF expression indirectly via regulation of MeCP2 expression and CREB activation.…”

Section: Epigenetics and Psychostimulant Addictionmentioning

confidence: 99%

Epigenetics and Psychostimulant Addiction

Schmidt

McGinty

West

et al. 2013

Cold Spring Harbor Perspectives in Medicine

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Chronic drug exposure alters gene expression in the brain and produces long-term changes in neural networks that underlie compulsive drug taking and seeking. Exactly how druginduced changes in synaptic plasticity and subsequent gene expression are translated into persistent neuroadaptations remains unclear. Emerging evidence suggests that complex drug-induced neuroadaptations in the brain are mediated by highly synchronized and dynamic patterns of gene regulation. Recently, it has become clear that epigenetic mechanisms contribute to drug-induced structural, synaptic, and behavioral plasticity by regulating expression of gene networks. Here we review how alterations in histone modifications, DNA methylation, and microRNAs regulate gene expression and contribute to psychostimulant addiction with a focus on the epigenetic mechanisms that regulate brain-derived neurotrophic factor (BDNF) expression following chronic cocaine exposure. Identifying epigenetic signatures that define psychostimulant addiction may lead to novel, efficacious treatments for drug craving and relapse. D rug addiction is a chronic, relapsing disorder that is characterized by compulsive drug seeking and taking despite adverse consequences (Mendelson and Mello 1996). The transition from recreational to chronic drug taking and the persistence of drug addiction are mediated, in part, by drug-induced alterations in gene expression profiles within the reward circuitry of the brain (Nestler 2001;Koob and Volkow 2010;. Therefore, elucidating the molecular mechanisms by which chronic drug exposure promotes stable changes in gene expression and ultimately drug-seeking behavior may aid in the development of novel pharmacotherapies for drug addiction. Recent studies indicate that epigenetic mechanisms contribute to drug-induced structural, synaptic, and behavioral plasticity by orchestrating expression of gene networks in discrete brain nuclei Russo et al. 2010). In this article, we review how chromatin remodeling, DNA methylation, and microRNAs regulate gene networks and contribute to cocaine addiction. A particular emphasis is placed on the epigenetic mechanisms regulating expression of brain-derived neurotrophic factor

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Human microRNAs miR-22, miR-138-2, miR-148a, and miR-488 Are Associated with Panic Disorder and Regulate Several Anxiety Candidate Genes and Related Pathways

Cited by 161 publications

References 51 publications

Temporal association of elevated cholecystokininergic tone and adolescent trauma is critical for posttraumatic stress disorder-like behavior in adult mice

Temporal association of elevated cholecystokininergic tone and adolescent trauma is critical for posttraumatic stress disorder-like behavior in adult mice

MicroRNA-Mediated Regulation and the Genetic Susceptibility to Anxiety Disorders

Epigenetics and Psychostimulant Addiction

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