Transgenic mice overexpressing the full-length neurotrophin receptor TrkC exhibit increased catecholaminergic neuron density in specific brain areas and increased anxiety-like behavior and panic reaction

Dierssen, Mara; Gratacòs, Mónica; Sahún, Ignasi; Martı́n, Miguel; Gallego, Xavier; Amador-Arjona, Alejandro; Lagrán, María Martínez de; Murtra, Patricia; Martı́, Eulàlia; Pujana, Miguel Ángel; Ferrer, Isidre; Dalfó, Esther; Martı́nez-Cué, Carmen; Flórez, Jesús; Torres-Peraza, Jesús F.; Alberch, Jordi; Maldonado, Rafaël; Fillat, Cristina; Estivill, Xavier

doi:10.1016/j.nbd.2006.07.015

Cited by 48 publications

(42 citation statements)

References 79 publications

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“…The neurotrophic support is critical for neuronal systems and its reduction may cause developmental alterations of the fear circuitry or impair neural adaptation to stress . Data from a transgenic mouse model overexpressing the full-length isoform of NTRK3 supports this hypothesis [Dierssen, et al, 2006] as these mice present anxiety-like behaviour and show increased cellularity in the LC and other catecholaminergic nuclei. Neurotrophin-3 has trophic effects on LC neurons and mediates the effect of stress and of some antidepressants on LC function and plasticity [Smith, et al, 1995].…”

Section: Discussionmentioning

confidence: 74%

“…These findings demonstrate that changes in regulatory elements that lead to minor variations in the dosage of proteins involved in neuronal pathways may play an important role in fine-tuning the activity of these proteins, contributing to the susceptibility to psychiatric disorders. This could be the case for NTRK3 that has recently been associated to anxiety-like behaviour in a mouse model overexpressing the full length of NTRK3 [Dierssen, et al, 2006]. Furthermore, posttranscriptional regulation of the truncated isoform of NTRK3 by two miRNAs (miR-9 and miR-125) has recently been demonstrated [Laneve, et al, 2007].…”

Section: Discussionmentioning

confidence: 92%

“…In particular, the neurotrophin-3 receptor gene (NTRK3, MIM#191316) is highly expressed in the locus coeruleus [King, et al, 1999], a brain structure that has an important function in the fear/alarm modulatory circuitry [Sullivan, et al, 1999]. Furthermore, overexpression of a full length isoform of 4 NTRK3 has been shown to contribute to anxiety-like behaviour in NTRK3 transgenic mice, whose anxious phenotype was reversed by the administration of benzodiazepines [Dierssen, et al, 2006;. Linkage and association studies suggest NTRK3 as a candidate gene also for other psychiatric disorders such as eating disorders or major depression [Camp, et al, 2005;Holmans, et al, 2007;Verma, et al, 2008].…”

Section: Introductionmentioning

confidence: 99%

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Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders

et al. 2009

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Genetic and functional data indicate that variation in the expression of the neurotrophin-3 receptor gene (NTRK3) may have an impact on neuronal plasticity suggesting a role for NTRK3 in the pathophysiology of anxiety disorders. MicroRNAs are post-transcriptional gene regulators that act by base pairing to specific sequences, usually at the 3'UTR of the target mRNA. Nucleotide variants at these sites might result in changes of gene expression contributing to disease susceptibility. We have investigated genetic variation in two different isoforms of NTRK3 as candidate susceptibility factors for anxiety by re-sequencing their 3'UTRs in patients with panic disorder, obsessive-compulsive disorder and controls. We have found the C allele of rs28521337, located in a functional target site for miR-485-3p in the truncated isoform of NTRK3, to be significantly associated with the hoarding phenotype of obsessive-compulsive disorder. Furthermore, we have also identified two new rare allelic variants in the 3'UTR of NTRK3, ss102661458 and ss102661460, each present only in a chomosome of a patient with panic disorder. The ss102661458 variant is located in a functional target site for miR-765, and the ss102661460 in functional target sites for two microRNAs, miR-509 and miR-128, the latter being a brain-enriched microRNA involved in neuronal differentiation and synaptic processing. Interestingly, these two variants significantly alter the microRNA-mediated regulation of NTRK3 and result in the recovery of gene expression. The reported data implicate microRNAs as key post-transcriptional regulators of NTRK3 and provide a framework for allele-specific microRNA regulation of NTRK3 in anxiety disorders.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders

et al. 2009

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“…Young adult (two to four months old) male wild-type (WT) and TgNTRK3 (Dierssen et al, 2006) mice were used in all experiments. The colony was maintained by crossing TgNTRK3 males with C57Bl/6SJL females (purchased from Jackson laboratory, Bar Harbor, Maine, USA).…”

Section: Animalsmentioning

confidence: 99%

“…NTRK3 gene has been associated with PAND and other psychiatric conditions in human genetic studies (Armengol et al, 2002;Gratacos et al, 2001;MuinosGimeno et al, 2009). We previously demonstrated that transgenic mice overexpressing the full-length NTRK3 (TgNTRK3 mouse model) recapitulate PAND phenotypes (Dierssen et al, 2006). Importantly, TgNTRK3 mice show fear memories that are resistant to contextual extinction, along with an altered neuronal activation in the hippocampus-amygdala-mPFC fear circuit (Santos et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Infralimbic Neurotrophin-3 Infusion Rescues Fear Extinction Impairment in a Mouse Model of Pathological Fear

D’Amico

Gener

Lagrán

et al. 2016

Neuropsychopharmacol

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The inability to properly extinguish fear memories constitutes the foundation of several anxiety disorders, including panic disorder. Recent findings show that boosting prefrontal cortex synaptic plasticity potentiates fear extinction, suggesting that therapies that augment synaptic plasticity could prove useful in rescue of fear extinction impairments in this group of disorders. Previously, we reported that mice with selective deregulation of neurotrophic tyrosine kinase receptor, type 3 expression (TgNTRK3) exhibit increased fear memories accompanied by impaired extinction, congruent with an altered activation pattern of the amygdala-hippocampus-medial prefrontal cortex fear circuit. Here we explore the specific role of neurotrophin 3 and its cognate receptor in the medial prefrontal cortex, and its involvement in fear extinction in a pathological context. In this study we combined molecular, behavioral, in vivo pharmacology and ex vivo electrophysiological recordings in TgNTRK3 animals during contextual fear extinction processes. We show that neurotrophin 3 protein levels are increased upon contextual fear extinction in wild-type animals but not in TgNTRK3 mice, which present deficits in infralimbic long-term potentiation. Importantly, infusion of neurotrophin 3 to the medial prefrontal cortex of TgNTRK3 mice rescues contextual fear extinction and ex vivo local application improves medial prefrontal cortex synaptic plasticity. This effect is blocked by inhibition of extracellular signal-regulated kinase phosphorylation through peripheral administration of SL327, suggesting that rescue occurs via this pathway. Our results suggest that stimulating neurotrophin 3-dependent medial prefrontal cortex plasticity could restore contextual fear extinction deficit in pathological fear and could constitute an effective treatment for fear-related disorders.

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Neurotrophic Support of Midbrain Dopaminergic Neurons

Halbach

Unsicker

2009

Advances in Experimental Medicine and Biology

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Transgenic mice overexpressing the full-length neurotrophin receptor TrkC exhibit increased catecholaminergic neuron density in specific brain areas and increased anxiety-like behavior and panic reaction

Cited by 48 publications

References 79 publications

Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders

Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders

Infralimbic Neurotrophin-3 Infusion Rescues Fear Extinction Impairment in a Mouse Model of Pathological Fear

Neurotrophic Support of Midbrain Dopaminergic Neurons

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