Essential Role for TrkB Receptors in Hippocampus-Mediated Learning

Minichiello, Liliana; Körte, Martin; Wolfer, David P; Kühn, Ralf; Unsicker, Klaus; Cestari, Vincenzo; Rossi-Arnaud, Clelia; Lipp, Hans‐Peter; Bonhoeffer, Tobias; Klein, Rüdiger

doi:10.1016/s0896-6273(00)80853-3

Cited by 748 publications

(700 citation statements)

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“…Normal locomotion on blockade of dopamine receptors revealed a dopamine deregulation in ACC mice as well. In these mutants, ADF is systemically deleted, whereas deletion of n-cofilin is controlled by the expression of a CaMKII-Cre transgene (21). In these transgenic mice, Cre is not expressed during brain development, and expression in adults is largely restricted to the telencephalon.…”

Section: Discussionmentioning

confidence: 99%

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Attention-Deficit/Hyperactivity Disorder–like Phenotype in a Mouse Model with Impaired Actin Dynamics

Zimmermann

Jene

Wolf

et al. 2015

Biological Psychiatry

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BACKGROUND: Actin depolymerizing proteins of the actin depolymerizing factor (ADF)/cofilin family are essential for actin dynamics, which is critical for synaptic function. Two ADF/cofilin family members, ADF and n-cofilin, are highly abundant in the brain, where they are present in excitatory synapses. Previous studies demonstrated the relevance of n-cofilin for postsynaptic plasticity, associative learning, and anxiety. These studies also suggested overlapping functions for ADF and n-cofilin. METHODS: We performed pharmacobehavioral, electrophysiologic, and electron microscopic studies on ADF and n-cofilin single mutants and double mutants (named ACC mice) to characterize the importance of ADF/cofilin activity for synapse physiology and mouse behavior. RESULTS: The ACC mice, but not single mutants, exhibited hyperlocomotion, impulsivity, and impaired working memory. Hyperlocomotion and impulsive behavior were reversed by methylphenidate, a psychostimulant commonly used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Also, ACC mice displayed a disturbed morphology of striatal excitatory synapses, accompanied by strongly increased glutamate release. Blockade of dopamine or glutamate transmission resulted in normal locomotion. CONCLUSIONS: Our study reveals that ADHD can result from a disturbed balance between excitation and inhibition in striatal circuits, providing novel insights into the mechanisms underlying this neurobehavioral disorder. Our results link actin dynamics to ADHD, suggesting that mutations in actin regulatory proteins may contribute to the etiology of ADHD in humans.

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Section: Discussionmentioning

confidence: 99%

“…In ACC mice, n-cofilin is deleted in a tissue-specific manner controlled by the expression of a CaMKII-Cre transgene (21). We next tested whether CaMKII-Cre is active in SNc dopamine neurons.…”

Section: N-cofilin Is Deleted In Only a Small Fraction Of Dopamine Nementioning

confidence: 99%

Attention-Deficit/Hyperactivity Disorder–like Phenotype in a Mouse Model with Impaired Actin Dynamics

Zimmermann

Jene

Wolf

et al. 2015

Biological Psychiatry

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“…15 In addition, learning and memory deficits have been demonstrated in mice with postnatal deletion of Ntrk2 in the forebrain, 16 and in Bdnf heterozygous knockout mice, 17 phenotypes that are likely to result from impaired neuronal plasticity in the hippocampus. 16,[18][19][20] We have previously screened 198 subjects with severe obesity and developmental delay for sequence variants in the coding region of NTRK2. 21 We identified a de novo heterozygous missense mutation, Y722C, in a subject with severe hyperphagia and obesity, impaired learning and memory and impaired nociception.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of human NTRK2 mutations identified in patients with severe early-onset obesity

et al. 2006

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Objective: The neurotrophin receptor TrkB has been implicated in the regulation of energy homeostasis in rodents. We have previously identified four rare missense mutations in the gene encoding TrkB, NTRK2, in 198 severely obese children with developmental delay. We have now undertaken a more detailed analysis of the in vitro functional consequences of the mutations identified: I98V, P660L, T821A and Y722C. Design: Wild-type and mutant TrkB receptor constructs were stably transfected into PC12 cells and the signaling responses to the endogenous ligand, brain-derived neurotrophic factor (BDNF), were examined by Western blotting of cell lysates. In the case of Y722C, PC12 cells stably expressing this mutant were studied for their ability to respond to BDNF by promoting neurite outgrowth and cell survival. Results: Further functional characterization of the previously reported Y722C TrkB mutation reveals impaired activation of mitogen-activated protein kinase, phospholipase C-g and Akt, as well as reduced BDNF-induced neurite outgrowth and cell survival in stably transfected PC12 cell lines. However, the signaling properties of I98V, P660L and T821A were all indistinguishable from wild type. Conclusion: We provide further evidence for the impairment in signaling by Y722C and show that as well as a loss of signaling, this mutation affects the ability of TrkB to promote neurite outgrowth in response to BDNF. Thus, impaired hypothalamic neurogenesis may contribute to the severe hyperphagia and obesity seen in the individual harboring the Y722C variant. The other three rare TrkB variants do not show reduced autophosphorylation or impaired downstream signaling in vitro and, as yet, it is unclear whether these variants contribute to obesity in these patients.

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“…BDNF, a major trophic factor in the CNS, is critical for the development and survival of certain neuronal populations. In addition to protecting neurons from damage caused by insults of various kinds, BDNF also modulates synaptic transmission and plays a role in synaptic plasticity, including LTP and certain forms of learning and memory processes in animal models [7,21,28,44,52,80]. Accordingly, conditions that may interfere with BDNF signaling may affect a variety of downstream neuronal functions and may contribute to neurodegenerative diseases, including Alzheimer's disease (AD) [13].…”

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confidence: 99%

Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

Tong

Balázs

Soi-ampornkul³

et al. 2008

Neurobiology of Aging

196

142

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The expression of IL-1 is elevated in the CNS in diverse neurodegenerative disorders, including Alzheimer's disease. The hypothesis was tested that IL-1β renders neurons vulnerable to degeneration by interfering with BDNF-induced neuroprotection. In trophic support-deprived neurons, IL-1β compromised the PI3-K/Akt pathway-mediated protection by BDNF and suppressed Akt activation. The effect was specific as in addition to Akt, the activation of MAPK/ ERK, but not PLCγ, was decreased. Activation of CREB, a target of these signaling pathways, was severely depressed by IL-1β. As the cytokine did not influence TrkB receptor and PLCγ activation, IL-1β might have interfered with BDNF signaling at the docking step conveying activation to the PI3-K/Akt and Ras/MAPK pathways. Indeed, IL-1β suppressed the activation of the respective scaffolding proteins IRS-1 and Shc; this effect might involve ceramide generation. IL-1-induced interference with BDNF neuroprotection and signal transduction was corrected, in part, by ceramide production inhibitors and mimicked by the cell-permeable C2-ceramide. These results suggest that IL-1β places neurons at risk by interfering with BDNF signaling involving a ceramide-associated mechanism. Keywords IL-1β; BDNF; signal transduction; cortical neuronsInterleukin-1 (IL-1) is a pluripotent proinflammatory cytokine that is a potent activator of host defense responses to infection and injury both in the periphery and the CNS [59]. However, IL-1 can also exacerbate damage in the CNS resulting from acute insults, such as © 2007 Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript cerebral ischemia and trauma, and circumstantial evidence is consistent with a similar role in chronic neurological diseases, such as multiple sclerosis, Parkinson's disease and Alzheimer's disease (AD) [48]. Furthermore, recent genetic studies highlighted the relevance of IL-1 in AD pathogenesis, showing that specific polymorphisms in the IL-1 gene cluster are associated with greatly increased risk for AD, especially for the earlier onset of the disease [23,50]. The view that inflammatory processes play an important role in pathogenesis has been supported by epidemiological studies, showing that certain antiinflammatory drugs result in a slower progression of the disease [2,8,43,77] and in transgenic AD models decrease the number of dystrophic neurites, activated microglia and IL-1 expression [35], although such drugs also modulate the production of the a...

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Essential Role for TrkB Receptors in Hippocampus-Mediated Learning

Cited by 748 publications

References 73 publications

Attention-Deficit/Hyperactivity Disorder–like Phenotype in a Mouse Model with Impaired Actin Dynamics

Attention-Deficit/Hyperactivity Disorder–like Phenotype in a Mouse Model with Impaired Actin Dynamics

Functional characterization of human NTRK2 mutations identified in patients with severe early-onset obesity

Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

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