Endogenous BDNF Protein Is Increased in Adult Rat Hippocampus after a Kainic Acid Induced Excitotoxic Insult but Exogenous BDNF Is Not Neuroprotective

Rudge, John S.; Mather, Pamela E.; Pasnikowski, Elizabeth; Cai, Na; Corcoran, T. L.; Acheson, Ann; Anderson, Keith D.; Lindsay, Ronald M.; Wiegand, Stanley J.

doi:10.1006/exnr.1997.6737

Cited by 129 publications

(87 citation statements)

References 53 publications

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“…1C). Thus, MF sprouting is activity-dependent.We next sought to determine whether or not picrotoxin induces an increase in expression of BDNF, another characteristic of epileptic hippocampus (Nawa et al, 1995;Elmer et al, 1998;Rudge et al, 1998;Vezzani et al, 1999). As expected, ELISA assay revealed that picrotoxin treatment significantly elevated the level of BDNF protein expression in the homogenates of slices, and the increase was blocked by tetrodotoxin ( Fig.…”

mentioning

confidence: 68%

“…Seizure-induced upregulation of BDNF mRNA (Isackson et al, 1991;Gall, 1993) and protein (Nawa et al, 1995;Elmer et al, 1998;Rudge et al, 1998;Vezzani et al, 1999) in the hippocampus is a common phenomenon across various experimental models of epilepsy. Nonetheless, evidence for a specific contribution of BDNF to MF sprouting is still controversial.…”

Section: Bdnf Is Causal In Inducing Mf Sproutingmentioning

confidence: 99%

“…One candidate of the responsible molecules is brainderived neurotrophic factor (BDNF), a member of the neurotrophin family, which has been implicated as a potent morphoregulator that controls axon branching (Cohen-Cory and Fraser, 1995;Gallo and Letourneau, 1998), dendritic growth (McAllister et al, 1995(McAllister et al, , 1997, spine density (Shimada et al, 1998;Tyler and Pozzo-Miller, 2001), and activity-dependent refinement of synapses (Cabelli et al, 1995;Horch et al, 1999). In epileptic hippocampus, granule cells display an upregulation of BDNF mRNA (Isackson et al, 1991;Gall, 1993) and protein (Nawa et al, 1995;Elmer et al, 1998;Rudge et al, 1998;Vezzani et al, 1999;Katoh-Semba et al, 2001) as well as the BDNF receptor tyrosine kinase (Trk)B mRNA (Bengzon et al, 1993), and phosphorylation of TrkB is also detected in the MF pathway . However, the causal relationship between BDNF and MF sprouting has been a contentious issue (Binder et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Brain-Derived Neurotrophic Factor Induces Hyperexcitable Reentrant Circuits in the Dentate Gyrus

Koyama¹,

Yamada²,

Fujisawa³

et al. 2004

J. Neurosci.

140

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Aberrant sprouting and synaptic reorganization of the mossy fiber (MF) axons are commonly found in the hippocampus of temporal lobe epilepsy patients and result in the formation of excitatory feedback loops in the dentate gyrus, a putative cellular basis for recurrent epileptic seizures. Using ex vivo hippocampal cultures, we show that prolonged hyperactivity induces MF sprouting and the resultant network reorganizations and that brain-derived neurotrophic factor (BDNF) is necessary and sufficient to evoke these pathogenic plasticities. Hyperexcitation induced an upregulation of BDNF protein expression in the MF pathway, an effect mediated by L-type Ca 2ϩ channels. The neurotrophin receptor tyrosine kinase (Trk)B inhibitor K252a or function-blocking anti-BDNF antibody prevented hyperactivity-induced MF sprouting. Even under blockade of neural activity, local application of BDNF to the hilus, but not other subregions, was capable of initiating MF axonal remodeling, eventually leading to dentate hyperexcitability. Transfecting granule cells with dominant-negative TrkB prevented axonal branching. Thus, excessive activation of L-type Ca 2ϩ channels causes granule cells to express BDNF, and extracellularly released BDNF stimulates TrkB receptors present on the hilar segment of the MFs to induce axonal branching, which may establish hyperexcitable dentate circuits.Key words: hippocampus; granule cell; mossy fiber; epilepsy; sprouting; BDNF IntroductionThe neural circuit in the dentate gyrus is a highly vulnerable organization. In the brains of patients and animal models of temporal lobe epilepsy, a widely recognized remodeling is the abnormal targeting of hippocampal mossy fibers (MFs), a phenomenon termed MF sprouting. In epileptic hippocampus, the MF axons often bifurcate in the hilar region, and the sprouted collaterals are ectopically guided into the inner molecular layer, where they synapse with the proximal segments of dendrites of granule cells (Cronin and Dudek, 1988;Sutula et al., 1988;de Lanerolle et al., 1989;Babb et al., 1991;Okazaki et al., 1995). Ultrastructural analysis reveals that most of these ectopic synapses are asymmetric (Cavazos et al., 2003) and terminate on dendritic spines (Buckmaster et al., 2002), both of which are typical of excitatory synapses. Thus, granule cells are interconnected, forming their excitatory loop chains in the dentate gyrus.This plastic remodeling is of particular importance in at least two neurological aspects. First, these abnormal recurrent circuits are functionally active (Molnar and Nadler, 1999;Lynch and Sutula, 2000) and cause hyperexcitation of the dentate gyrus (Wuarin and Dudek, 1996;Feng et al., 2003), whereby cortical signal is excessively amplified before reaching the hippocampus. These anatomical aberrations, hence, are potential epileptogenic foci, and MF sprouting could be a therapeutic target of temporal lobe epilepsy . Second, many experimental studies consistently indicate that convulsants with different mechanisms of action, e.g., pilocarpine, kainate,...

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mentioning

confidence: 68%

Section: Bdnf Is Causal In Inducing Mf Sproutingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Brain-Derived Neurotrophic Factor Induces Hyperexcitable Reentrant Circuits in the Dentate Gyrus

Koyama¹,

Yamada²,

Fujisawa³

et al. 2004

J. Neurosci.

140

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“…Status epilepticus leads to a dramatic increase of BDNF immunoreactivity in the mossy fiber pathway (Wetmore et al, 1994;Yan et al, 1997;Rudge et al, 1998;Katoh-Semba et al, 1999). Whether BDNF is increased only in mossy fiber boutons already immunoreactive for BDNF or whether previously immunonegative boutons become immunopositive is not known.…”

Section: Status Epilepticus Alters the Pattern Of Bdnf Immunoreactivimentioning

confidence: 99%

Localization of Brain-Derived Neurotrophic Factor to Distinct Terminals of Mossy Fiber Axons Implies Regulation of Both Excitation and Feedforward Inhibition of CA3 Pyramidal Cells

Danzer

McNamara²

2004

J. Neurosci.

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Hippocampal dentate granule cells directly excite and indirectly inhibit CA3 pyramidal cells via distinct presynaptic terminal specializations of their mossy fiber axons. This mossy fiber pathway contains the highest concentration of brain-derived neurotrophic factor (BDNF) in the CNS, yet whether BDNF is positioned to regulate the excitatory and/or inhibitory pathways is unknown. To localize BDNF, confocal microscopy of green fluorescent protein transgenic mice was combined with BDNF immunohistochemistry. Approximately half of presynaptic granule cell-CA3 pyramidal cell contacts were found to contain BDNF. Moreover, enhanced neuronal activity virtually doubled the percentage of BDNF-immunoreactive terminals contacting CA3 pyramidal cells. To our surprise, BDNF was also found in mossy fiber terminals contacting inhibitory neurons. These studies demonstrate that mossy fiber BDNF is poised to regulate both direct excitatory and indirect feedforward inhibitory inputs to CA3 pyramdal cells and reveal that seizure activity increases the pool of BDNFexpressing granule cell presynaptic terminals contacting CA3 pyramidal cells.

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“…One of candidate molecules linking between neural activity and the sprouting is brain-derived neurotrophic factor (BDNF). Expression levels of BDNF mRNA (Isackson et al, 1991;Gall, 1993) and protein (Nawa et al, 1995;Gall et al, 1993;Elmer et al, 1998;Rudge et al, 1998;Vezzani et al, 1999) are upregulated in epileptic animal models (for review, see Binder et al, 2001). Because the induction of BDNF protein is most evident in the MF pathway, we hypothesize that activity-dependent release of BDNF in the dentate hilus induces the formation of MF protrusions.…”

Section: Induction Of Mossy Fiber Sprouting By Abnormal Axon Guidancementioning

confidence: 99%

Mossy Fiber Sprouting as a Potential Therapeutic Target for Epilepsy

Koyama

Ikegaya²

2004

CNR

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Hippocampal mossy fibers, axons of dentate granule cells, converge in the dentate hilus and run through a narrow area called the stratum lucidum to synapse with hilar and CA3 neurons. In the hippocampal formation of temporal lobe epilepsy patients, however, this stereotyped pattern of projection is often collapsed; the mossy fibers branch out of the dentate hilus and abnormally innervate the dentate inner molecular layer, a phenomenon that is termed mossy fiber sprouting. Experimental studies have replicated this sprouting in animal models of temporal lobe epilepsy, including kindling and pharmacological treatment with convulsants. Because these axon collaterals form recurrent excitatory inputs into dendrites of granule cells, the circuit reorganization is assumed to cause epileptiform activity in the hippocampus, whereas some recent studies indicate that the sprouting is not necessarily associated with early-life seizures. Here we review the mechanisms of mossy fiber sprouting and consider its potential contribution to epileptogenesis. Based on recent findings, we propose that the sprouting can be regarded as a result of disruption of the molecular mechanisms underlying the axon guidance. We finally focus on the possibility that prevention of the abnormal sprouting might be a new strategy for medical treatment with temporal lobe epilepsy.

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Endogenous BDNF Protein Is Increased in Adult Rat Hippocampus after a Kainic Acid Induced Excitotoxic Insult but Exogenous BDNF Is Not Neuroprotective

Cited by 129 publications

References 53 publications

Brain-Derived Neurotrophic Factor Induces Hyperexcitable Reentrant Circuits in the Dentate Gyrus

Brain-Derived Neurotrophic Factor Induces Hyperexcitable Reentrant Circuits in the Dentate Gyrus

Localization of Brain-Derived Neurotrophic Factor to Distinct Terminals of Mossy Fiber Axons Implies Regulation of Both Excitation and Feedforward Inhibition of CA3 Pyramidal Cells

Mossy Fiber Sprouting as a Potential Therapeutic Target for Epilepsy

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