Increased production of the TrkB protein tyrosine kinase receptor after brain insults

Merlio, Jean-Philippe; Ernfors, Patrik; Kokaia, Zaal; Middlemas, David S.; Bengzon, Johan; Kokaia, Mérab; Smith, Maj‐Lis; Siesjö, Bo K.; Hunter, Tony; Lindvall, Olle; Persson, Håkan

doi:10.1016/0896-6273(93)90307-d

Cited by 330 publications

(98 citation statements)

References 62 publications

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“…It has also been shown that striatal mRNA of TrkB is transiently elevated after seizures (Merlio et al, 1993;Salin et al, 1995) and that epileptiform activity induces a strong upregulation of cortical TrkB (Wyneken et al, 2001(Wyneken et al, , 2003. All these data support the idea that TrkB/BDNF signaling pathway is a key factor in the development and control of seizures, although the question whether BDNF has a permissive or protective function in the epileptogenesis is still debated.…”

Section: Introductionsupporting

confidence: 63%

TrkB/BDNF-Dependent Striatal Plasticity and Behavior in a Genetic Model of Epilepsy: Modulation by Valproic Acid

Ghiglieri

Sgobio

Patassini

et al. 2010

Neuropsychopharmacol

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In mice lacking the central domain of the presynaptic scaffold Bassoon the occurrence of repeated cortical seizures induces cell-typespecific plasticity changes resulting in a general enhancement of the feedforward inhibition within the striatal microcircuit. Early antiepileptic treatment with valproic acid (VPA) reduces epileptic attacks, inhibits the emergence of pathological form of plasticity in fast-spiking (FS) interneurons and restores physiological striatal synaptic plasticity in medium spiny (MS) neurons. Brain-derived neurotrophic factor (BDNF) is a key factor for the induction and maintenance of synaptic plasticity and it is also implicated in the mechanisms underlying epilepsy-induced adaptive changes. In this study, we explore the possibility that the TrkB/BDNF system is involved in the striatal modifications associated with the Bassoon gene (Bsn) mutation. In epileptic mice abnormal striatum-dependent learning was paralleled by higher TrkB levels and an altered distribution of BDNF. Accordingly, subchronic intrastriatal administration of k252a, an inhibitor of TrkB receptor tyrosine kinase activity, reversed behavioral alterations in Bsn mutant mice. In addition, in vitro manipulations of the TrkB/BDNF complex by k252a, prevented the emergence of pathological plasticity in FS interneurons. Chronic treatment with VPA, by reducing seizures, was able to rebalance TrkB to control levels favoring a physiological redistribution of BDNF between MS neurons and FS interneurons with a concomitant recovery of striatal plasticity. Our results provide the first indication that BDNF is involved in determining the striatal alterations occurring in the early-onset epileptic syndrome associated with the absence of presynaptic protein Bassoon.

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Section: Introductionsupporting

confidence: 63%

TrkB/BDNF-Dependent Striatal Plasticity and Behavior in a Genetic Model of Epilepsy: Modulation by Valproic Acid

Ghiglieri

Sgobio

Patassini

et al. 2010

Neuropsychopharmacol

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“…Treatment with FK506 was previously shown to enhance phospho-cAMP response element binding protein (pCREB) immunoreactivity in hippocampal neurons and striatum slices (Merlio et al, 1993). pCREB is known to mediate the expression of a variety of genes, including brain-derived neurotrophic factor (BDNF) (Beck et al, 1994), nerve growth factor (NGF) (Tao et al, 1998), c-fos (Walton et al, 1996), and bcl-2 (Wilson et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

Almeida

Domingues

Rodrigues

et al. 2004

Neurobiology of Disease

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The mitochondrial toxin 3-nitropropionic acid (3-NP) has been largely used to study neurodegenerative disorders in which bioenergetic defects are implicated. In the present study, we analyzed the molecular pathways involved in FK506 neuroprotection against cell death induced by 3-NP, using cultured cortical neurons. 3-NP induced cytochrome c release and increased caspases -2, -3, -8, and -9-like activities, although, calpain activity was not significantly affected. FK506 decreased cytochrome c release and caspase-3-like activity induced by 3-NP, without changing the activities of other caspases. FK-506 also decreased the number of apoptotic neurons, determined by Hoechst. Under these conditions, FK506 alone significantly reduced calcineurin activity by about 50%. Our results also showed a decrease in mitochondrial Bax and an increase in mitochondrial Bcl-2 levels upon exposure to FK506 and 3-NP. However, no significant changes occurred in total Bcl-2 and Bax levels. Altogether, the results suggest that FK506 neuroprotection against 3-NP-induced apoptosis is associated with the redistribution of Bcl-2 and Bax in the mitochondrial membrane. D

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“…Indeed, there is abundant evidence supporting the concept that neurotrophins and their receptors have a protective effect on many neuronal populations after injury (Sendtner et al, 1992;Yan et al, 1992Yan et al, , 1993Koliatsos et al, 1993;Arenas and Persson, 1994;Li et al, 1994). For instance, it has been shown that axotomy results in changes in the expression of neurotrophins and p75 and Trk receptors in neurons, glial cells, and target tissues (Heumann et al, 1987;Ernfors et al, 1989;Frisén et al, 1992Frisén et al, , 1993Meyer et al, 1992;Beck et al, 1993;Funakoshi et al, 1993;Koliatsos et al, 1993;Mearow et al, 1993;Merlio et al, 1993;Piehl et al, 1994;Kobayashi et al, 1996). Furthermore, exogenously administered neurotrophins can rescue neurons from injury-induced cell death in axotomy paradigms (Sendtner et al, 1992;Yan et al, 1992;Koliatsos et al, 1993Koliatsos et al, , 1994Yan et al, 1993;Arenas and Persson, 1994).…”

Section: Abstract: Trkb; Cns; Cell Death; Axotomy; Hippocampus; Motomentioning

confidence: 99%

TrkB Signaling Is Required for Postnatal Survival of CNS Neurons and Protects Hippocampal and Motor Neurons from Axotomy-Induced Cell Death

et al. 1997

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Newborn mice carrying targeted mutations in genes encoding neurotrophins or their signaling Trk receptors display severe neuronal deficits in the peripheral nervous system but not in the CNS. In this study, we show that trkB (Ϫ/Ϫ) mice have a significant increase in apoptotic cell death in different regions of the brain during early postnatal life. The most affected region in the brain is the dentate gyrus of the hippocampus, although elevated levels of pyknotic nuclei were also detected in cortical layers II and III and V and VI, the striatum, and the thalamus. Furthermore, axotomized hippocampal and motor neurons of trkB (Ϫ/Ϫ) mice have significantly lower survival rates than those of wild-type littermates. These results suggest that neurotrophin signaling through TrkB receptors plays a role in the survival of CNS neurons during postnatal development. Moreover, they indicate that TrkB receptor signaling protects subpopulations of CNS neurons from injury-and axotomy-induced cell death. Key words: TrkB; CNS; cell death; axotomy; hippocampus; motor neuronNeurotrophins, including nerve growth factor (NGF), brainderived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5, and NT-6, have been shown to promote neuronal survival of a variety of neuronal populations (Fariñas and Reichardt, 1996). Mutant mice lacking the genes encoding each of these neurotrophins or their receptors have illustrated the exquisite requirement of neurotrophin signaling for the survival of distinct neuronal populations in the peripheral nervous system during embryonic development (Snider, 1994;Barbacid, 1995;Fariñas and Reichardt, 1996). However, very few defects have been detected in the CNS of these mutant mice.It has been suggested (Snider, 1994;Fariñas and Reichardt, 1996) that the absence of CNS defects in these animals might be attributable to the significant overlap in the pattern of TrkB and TrkC receptors in CNS neurons Merlio et al., 1992). However, this hypothesis seems unlikely, because double mutant mice lacking both of these Trk receptors do not show any obvious defects in the CNS, at least during embryonic development (Silos-Santiago et al., 1997). These observations suggest that the growth factor requirements of CNS neurons are more complex than those of the periphery. Another possibility is that CNS neurons require only neurotrophin support during postnatal development or even in adult animals. Alternatively, the role of neurotrophins in the CNS might involve aspects of neuronal function other than survival. Indeed, neurotrophin signaling has been implicated in physiological events such as synthesis of neuroactive substances (Lindsay and Harmar, 1989;Ip et al., 1993;Nawa et al., 1993Nawa et al., , 1994Jones et al., 1994;Marty et al., 1996), synaptic efficacy and rearrangement (Lohof et al., 1993;Cabelli et al., 1995;Kang and Schuman, 1995;Korte et al., 1995;Lesser and Lo, 1995;Levine et al., 1995;Lo, 1995;Thoenen, 1995;Patterson et al., 1996) and modulation of dendritic and axonal growth (Diamond et al., 1992;Schnell ...

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Increased production of the TrkB protein tyrosine kinase receptor after brain insults

Cited by 330 publications

References 62 publications

TrkB/BDNF-Dependent Striatal Plasticity and Behavior in a Genetic Model of Epilepsy: Modulation by Valproic Acid

TrkB/BDNF-Dependent Striatal Plasticity and Behavior in a Genetic Model of Epilepsy: Modulation by Valproic Acid

FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

TrkB Signaling Is Required for Postnatal Survival of CNS Neurons and Protects Hippocampal and Motor Neurons from Axotomy-Induced Cell Death

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