Epilepsy‐induced Changes in Signaling Systems of Human and Rat Postsynaptic Densities

Wyneken, Úrsula; Marengo, Juan-Jose; Villanueva, Sandra; Soto, Dagoberto; Sandoval, Rodrigo; Gundelfinger, Eckart D.; Orrego, Fernando

doi:10.1046/j.1528-1157.2003.17602.x

Cited by 37 publications

(24 citation statements)

References 12 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: Introductionmentioning

confidence: 62%

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: Introductionmentioning

confidence: 62%

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 addition, the majority of striatal neurons are inhibitory, and effects of BDNF have been shown to be cell-type-specific Rauskolb et al 2010;Rutherford et al 1998). Furthermore, whether TrkB levels are up or down-regulated or left unaffected after epileptic seizures has been reported to depend on both BDNF levels and the mode of seizure activity (Unsain et al 2009;2008;Wyneken et al 2003;Yokoi et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Hippocampal enlargement in Bassoon-mutant mice is associated with enhanced neurogenesis, reduced apoptosis, and abnormal BDNF levels

et al. 2011

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Mice mutant for the presynaptic protein Bassoon develop epileptic seizures and an altered pattern of neuronal activity that is accompanied by abnormal enlargement of several brain structures, with the strongest size increase in hippocampus and cortex. Using manganese-enhanced magnetic resonance imaging, an abnormal brain enlargement was found, which is first detected in the hippocampus 1 month after birth and amounts to an almost 40% size increase of this structure after 3 months. Stereological quantification of cell numbers revealed that enlargement of the dentate gyrus and the hippocampus proper is associated with larger numbers of principal neurons and of astrocytes. In search for the underlying mechanisms, an approximately 3-fold higher proportion of proliferation and survival of new-born cells in the dentate gyrus was found to go hand in hand with similarly larger numbers of doublecortin-positive cells and reduced numbers of apoptotic cells in the dentate gyrus and the hippocampus proper. Enlargement of the hippocampus and of other forebrain structures was accompanied by increased levels of brain-derived neurotrophic factor (BDNF). These data show that hippocampal overgrowth in Bassoon-mutant mice arises from a dysregulation of neurogenesis and apoptosis that might be associated with unbalanced BDNF levels.

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“…It is known that neuronal activation, or increases in cAMP and intracellular Ca 2 + , lead to the translocation of TrkB from the cytoplasm to the plasma membrane (MeyerFranke et al, 1998;Ji et al, 2005), and that excitation in experimental and human epilepsy greatly increases the TrkB content in PSDs (Wyneken et al, 2001(Wyneken et al, , 2003. As the increase of TrkB and BDNF is associated with neuronal activation, the decrease of TrkB in PSDs observed here is unlikely to be due to a decreased incorporation, but rather to an increased endocytosis of the BDNF/TrkB complex.…”

Section: Decrease Of Trkb In Psdsmentioning

confidence: 99%

Clinically Relevant Doses of Fluoxetine and Reboxetine Induce Changes in the TrkB Content of Central Excitatory Synapses

Wyneken

Sandoval

et al. 2006

Neuropsychopharmacol

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We have studied the effect of low doses of two widely used antidepressants, fluoxetine (Flx) and reboxetine (Rbx), on excitatory synapses of rat brain cortex and hippocampus. After 15 days of Flx treatment (0.67 mg/kg/day), its plasma level was 20.775.6 ng/ml. Analysis of postsynaptic densities (PSDs) by immunoblotting revealed no changes in the glutamate receptor subunits GluR1, NR1, NR2A/ B, mGluR1a nor in the neurotrophin receptor p75 NTR . However, the brain-derived neurotrophic factor (BDNF) receptor TrkB decreased by 42.876%, and remained decreased after 6 weeks of treatment. The BDNF and TrkB content in homogenates of cortex and hippocampus began to rise at 9 and 15 days, respectively, and remained high for up to 6 weeks. Similar results were obtained following chronic Rbx administration at 0.128 mg/kg/day. We propose that BDNF, whose synthesis is increased by antidepressants, and which is in part released at synaptic sites, binds to TrkB in PSDs, leading to the internalization of the BDNF-TrkB complex and, thus, to a decrease of TrkB in the PSDs. This was paralleled by greater levels of phosphorylated (ie activated) TrkB in the light membrane fraction, that contains signaling endosomes. The retrograde transport of endocyted BDNF/TrkB complexes from spines to cell bodies, where it activates the synthesis of more BDNF, is a protracted process, potentially requiring several cycles of TrkB/BDNF complex endocytosis and transport. This positive feedback mechanism may help explain the time-lag between drug administration and its therapeutic effect, that is, the antidepressant drug paradox.

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Epilepsy‐induced Changes in Signaling Systems of Human and Rat Postsynaptic Densities

Cited by 37 publications

References 12 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

Hippocampal enlargement in Bassoon-mutant mice is associated with enhanced neurogenesis, reduced apoptosis, and abnormal BDNF levels

Clinically Relevant Doses of Fluoxetine and Reboxetine Induce Changes in the TrkB Content of Central Excitatory Synapses

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