5′ UTR-region SNP in the NTRK3 gene is associated with panic disorder

Armengol, Lluı́s; Gratacòs, Mónica; Pujana, Miguel Ángel; Ribasés, Marta; Martín‐Santos, Rocío; Estivill, Xavier

doi:10.1038/sj.mp.4001134

Cited by 29 publications

(13 citation statements)

References 8 publications

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“…Interestingly, there is evidence that ntrk3 promotes the survival of postmitotic neurons (22). Moreover, recent studies have linked variations in this gene, SNPs, to anxiety disorders (23)(24)(25). Taken together, these results suggest that ntrk3, which showed a lifelong change in gene expression after FGF2, is involved in cell survival in early hippocampal development and associated with anxiety-like behavior.…”

Section: Discussionsupporting

confidence: 57%

Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals

Turner

Clinton

Thompson

et al. 2011

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

112

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Individuals with mood disorders exhibit alterations in the fibroblast growth factor system, including reduced hippocampal fibroblast growth factor-2 (FGF2). It is difficult, however, to pinpoint whether these alterations are a cause or consequence of the disorder. The present study asks whether FGF2 administered the day after birth has long-lasting effects on hippocampal development and emotionality. We show that early-life FGF2 shifts the pace of neurogenesis, with an early acceleration around weaning followed by a deceleration in adulthood. This, in turn, results in a denser dentate gyrus with more neurons. To assess the impact of early-life FGF2 on emotionality, we use rats selectively bred for differences in locomotor response to novelty. Selectively bred low-responder (bLR) rats show low levels of novelty-induced locomotion and exhibit high levels of anxiety-and depression-like behavior compared with their selectively bred high-responder counterparts. Early-life FGF2 decreased anxiety-like behavior in highly anxious bLRs without altering other behaviors and without affecting high-responder rats. Laser capture microscopy of the dentate gyrus followed by microarray analysis revealed genes that were differentially expressed in bLRs exposed to early-life FGF2 vs. vehicle-treated bLRs. Some of the differentially expressed genes that have been positively associated with anxiety were down-regulated, whereas genes that promote cell survival were up-regulated. Overall, these results show a key role for FGF2 in the developmental trajectory of the hippocampus as well as the modulation of anxiety-like behavior in adulthood, and they point to potential downstream targets for the treatment of anxiety disorders. elevated plus maze | gene expression microarray H uman postmortem studies suggest a role for the fibroblast growth factor (FGF) system in the pathophysiology of mood disorders. The expression of several members of the FGF family was altered in the forebrain of patients with major depressive disorder (MDD). Specifically, FGF2 mRNA expression was down-regulated in cortical areas and the hippocampus in MDD compared with controls (1, 2). The hippocampus seems to be particularly affected in MDD (3). A potential role for FGF2 in depression and anxiety disorders was first suggested by pharmacological studies in rodents, which showed that administration of antidepressant and anxiolytic drugs can increase FGF2 expression in the hippocampus (3-6). We then asked whether FGF2 is a modulator of emotionality in rodents and discovered that repeated administration of FGF2 was both antidepressant and anxiolytic (7,8).Using rats selectively bred for differences in novelty-seeking, we found that hippocampal expression of FGF2 mRNA was higher in high responders to novelty (bHRs) than in the low responders to novelty (bLRs). The bHRs have higher FGF2 levels and exhibit less anxiety-like behavior, whereas the bLRs exhibit more anxiety-like behavior. FGF2 seems to be a protective factor against anxiety-like behavior in the adult (7). Th...

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Section: Discussionsupporting

confidence: 57%

Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals

Turner

Clinton

Thompson

et al. 2011

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

112

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“…Additionally, ISLR2 sits on the cell membrane, aids in the guiding of axons, and can facilitate the activation of trk receptors, including NTRK3 (47,48). In addition to its involvement in our theoretically motivated focus on neuroplasticity, NTRK3 genetic variation has been linked to human psychopathology, including childhood-onset mood disorders (49)(50)(51)(52), and via its extracellular domain may provide an accessible drug target. Taken together, these findings implicate NTRK3 as a prominent target for future mechanistic studies examining childhood AT.…”

Section: Resultsmentioning

confidence: 99%

Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates

Fox

Oler

Shelton

et al. 2012

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

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Children with anxious temperament (AT) are particularly sensitive to new social experiences and have increased risk for developing anxiety and depression. The young rhesus monkey is optimal for studying the origin of human AT because it shares with humans the genetic, neural, and phenotypic underpinnings of complex social and emotional functioning. In vivo imaging in young monkeys demonstrated that central nucleus of the amygdala (Ce) metabolism is relatively stable across development and predicts AT. Transcriptome-wide gene expression, which reflects combined genetic and environmental influences, was assessed within the Ce. Results support a maladaptive neurodevelopmental hypothesis linking decreased amygdala neuroplasticity to early-life dispositional anxiety. For example, high AT individuals had decreased mRNA expression of neurotrophic tyrosine kinase, receptor, type 3 (NTRK3). Moreover, variation in Ce NTRK3 expression was inversely correlated with Ce metabolism and other AT-substrates. These data suggest that altered amygdala neuroplasticity may play a role the early dispositional risk to develop anxiety and depression.positron-emission tomography | microarray | brain imaging T he ability to identify brain mechanisms underlying the risk during childhood for developing anxiety and depression is critical for establishing novel early-life interventions aimed at preventing the chronic and debilitating outcomes associated with these common illnesses. To this end, we have optimized a model of anxious temperament (AT), the conserved at-risk phenotype, in young developing rhesus monkeys (1-4). The rhesus monkey is ideal for studying the origin of human AT because these species share the genetic, neural, and phenotypic underpinnings of complex social and emotional functioning (5-10). Importantly, the rhesus developmental model bridges the critical gap between human psychopathology and rodent models, allowing for translation to humans by using in vivo imaging measures and translation to rodents by using ex vivo molecular methods. Thus, the unique hypotheses that can be generated from the rhesus model are invaluable in guiding both imaging studies in children and mechanistic efforts in rodents.Of particular relevance to the AT rhesus model is the relatively recent evolutionary divergence between rhesus monkeys and humans (25 million years) compared with rodents and humans (70 million years) (5). This evolutionary closeness is reflected in the species' similarities in social and emotional behaviors. These homologies, instantiated in their conserved genetic and neural systems, underlie the ability of both humans and rhesus monkeys to form and maintain the relationships necessary for living in complex social environments. In this regard, the experience of anxiety has evolved in primates to motivate the formation of long-lasting attachment bonds that serve to increase security and group cohesion. The comparable rearing practices shared by these species (e.g., close mother-infant bonding) promote early social/emotional le...

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“…In 2001, an interesting cytogenetic study was published in Cell: Gratacòs et al (2001) reported the occurrence of a 17 Mb region duplication on chromosome 15q24-26 (DUP25) spanning about 60 genes linked to a panic disorder subtype with joint laxity and mitral valve prolapse in seven Spanish families. Additionally, a single nucleotide polymorphism in the 5 0 untranslated region (UTR) of the neurotrophin 3 (NTRK3) gene located in this duplicated chromosomal region was found to be significantly associated with PD (Armengol et al 2002). However, the initial duplication finding could not be replicated in independent samples so far (Tabiner et al 2003;Weiland et al 2003;Schumacher et al 2003;Henrichsen et al 2004;Zhu et al 2004).…”

Section: Anxiety Disordersmentioning

confidence: 93%

Genomic structural variation in affective, anxiety, and stress-related disorders

2014

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Anxiety and stress-related disorders are common and debilitating mental diseases. Genetic factors as well as environmental factors and life events contribute to their pathogenesis and partly mediate treatment response. However, these disorders are clinically heterogeneous, genetically complex, and the exact genetic causes are still unclear. Recently, some evidence has emerged for structural variation including copy number variants and small deletions/duplications to be associated with mental disorders. Here, the current state of knowledge on the role of genomic structural variation in affective, anxiety and stress-related disorders is reviewed, followed by a critical discussion of present methods to detect structural changes, future directions, and clinical implications including a potential role in personalized medicine.

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5′ UTR-region SNP in the NTRK3 gene is associated with panic disorder

Cited by 29 publications

References 8 publications

Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals

Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals

Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates

Genomic structural variation in affective, anxiety, and stress-related disorders

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