Nerve Growth Factor Accelerates Seizure Development, Enhances Mossy Fiber Sprouting, and Attenuates Seizure-Induced Decreases in Neuronal Density in the Kindling Model of Epilepsy

Adams, Beth; Sazgar, Mona; Osehobo, Philip; Zee, Catharina E.E.M. Van der; Diamond, Jack; Fahnestock, Margaret; Racine, R.

doi:10.1523/jneurosci.17-14-05288.1997

Cited by 116 publications

(50 citation statements)

References 62 publications

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“…In addition to its role in excitability, there is evidence that Src participates in neurotrophin signaling (33,34). Neurotrophins such as nerve growth factor have been shown to play a role in the morphologic rearrangements that accompany seizure development in the kindling model of epilepsy (35). It is therefore possible that Src activation also may contribute to the functional synaptic reorganization believed to take place in epilepsy.…”

Section: Resultsmentioning

confidence: 99%

A role for Src kinase in spontaneous epileptiform activity in the CA3 region of the hippocampus

Sanna

Berton²,

Cammalleri³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Members of the Src family of nonreceptor protein tyrosine kinases (PTKs) have been implicated in the regulation of cellular excitability and synaptic plasticity. We have investigated the role of these PTKs in in vitro models of epileptiform activity. Spontaneous epileptiform discharges were induced in vitro in the CA3 region of rat hippocampal slices by superfusion with the potassium channel blocker 4-aminopyridine in Mg 2؉ -free medium. In hippocampal slices treated in this fashion, Src kinase activity was increased and the frequency of epileptiform discharges could be greatly reduced by inhibitor of the Src family of PTKs, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo T he epilepsies are heterogeneous disorders characterized by recurrent synchronous discharges of large neuronal populations. Prominent features of the natural history of these pathologies are functional changes leading to the development of areas of low seizure threshold (epileptic foci) and the evolution toward more pervasive and malignant forms. In the present study, we investigated the role of nonreceptor protein tyrosine kinases (PTKs) of the Src family in the generation of spontaneous epileptiform activity in the CA3 region of rat hippocampal slices. Members of this family of PTKs are expressed in the central nervous system and have been implicated in the regulation of glutamate N-methyl-D-aspartate (NMDA) receptors, affecting in turn neural excitability and plasticity (1-3). In fact, phosphorylation of certain NMDA NR2 subunits by Src and the related nonreceptor PTK Fyn has been shown to increase NMDA receptor channel activity (1, 4). Enhanced NMDA responses have been observed in the kindling model of epilepsy (5-8) and in human epilepsy (9). Activation of Src also induces potentiation of non-NMDA glutamate receptor responses in an NMDAand Ca 2ϩ -dependent manner (1). Observations with mice in which Fyn was either genetically deleted or overexpressed also support a role for Src-family PTKs in the induction of kindling (10, 11), a process in which NMDA receptors have been shown to play a critical role (12, 13).Depletion of extracellular Mg 2ϩ from hippocampal slices results in enhancement of synaptically evoked responses in CA1 and CA3 and the appearance of spontaneous paroxysmal depolarization shifts in both areas (5, 14-16), whereas 4-aminopyridine (4-AP) induces epileptiform activity by enhancing the release of excitatory and inhibitory amino acids (17-19). We induced epileptiform activity in rat hippocampal slices with Mg 2ϩ -free medium in the presence of the potassium channel blocker 4-AP, a model of epileptogenesis previously used in neocortical slice preparations (17).Application of Mg 2ϩ -free medium and 4-AP induced robust bursting in the CA3. Src kinase activity was induced in such a model, and spontaneous epileptiform activity could be strongly reduced by the Src-family PTK inhibitor (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4-d]pyrimidine (PP2) also known as AG 1879 (20). In some experiments, hippocampal slices were tr...

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Section: Resultsmentioning

confidence: 99%

A role for Src kinase in spontaneous epileptiform activity in the CA3 region of the hippocampus

Sanna

Berton²,

Cammalleri³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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“…These same processes contribute to pathologies, such as Alzheimer's disease (Wu et al, 2014), sudden cardiac death (for review, see Vaseghi and Shivkumar, 2008), autonomic dysreflexia after spinal cord injury (Krenz et al, 1999;Marsh et al, 2002;Wanigasekara and Keast, 2006), and exacerbation of epilepsy (Noebels, 1984;Davenport et al, 1990; Van der Zee et al, 1995;Adams et al, 1997;Scharfman et al, 1999;Pitkänen and Sutula, 2002;Sierra et al, 2015). Hyperinnervation of visceral tissue and bone is a characteristic of some of the most agonizing forms of pain (Woolf, 1996;Jimenez-Andrade et al, 2010, Bloom et al, 2011Ló pez-Á lvarez et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

The Adaptor Protein CD2AP Is a Coordinator of Neurotrophin Signaling-Mediated Axon Arbor Plasticity

Harrison¹,

Venkat

Lamb

et al. 2016

J. Neurosci.

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Growth of intact axons of noninjured neurons, often termed collateral sprouting, contributes to both adaptive and pathological plasticity in the adult nervous system, but the intracellular factors controlling this growth are largely unknown. An automated functional assay of genes regulated in sensory neurons from the rat in vivo spared dermatome model of collateral sprouting identified the adaptor protein CD2-associated protein (CD2AP; human CMS) as a positive regulator of axon growth. In non-neuronal cells, CD2AP, like other adaptor proteins, functions to selectively control the spatial/temporal assembly of multiprotein complexes that transmit intracellular signals. Although CD2AP polymorphisms are associated with increased risk of late-onset Alzheimer's disease, its role in axon growth is unknown. Assessments of neurite arbor structure in vitro revealed CD2AP overexpression, and siRNA-mediated knockdown, modulated (1) neurite length, (2) neurite complexity, and (3) growth cone filopodia number, in accordance with CD2AP expression levels. We show, for the first time, that CD2AP forms a novel multiprotein complex with the NGF receptor TrkA and the PI3K regulatory subunit p85, with the degree of TrkA:p85 association positively regulated by CD2AP levels. CD2AP also regulates NGF signaling through AKT, but not ERK, and regulates long-range signaling though TrkA ϩ /RAB5 ϩ signaling endosomes. CD2AP mRNA and protein levels were increased in neurons during collateral sprouting but decreased following injury, suggesting that, although typically considered together, these two adult axonal growth processes are fundamentally different. These data position CD2AP as a major intracellular signaling molecule coordinating NGF signaling to regulate collateral sprouting and structural plasticity of intact adult axons.Key words: collateral sprouting; nerve growth factor; neural plasticity; signalosome; spared dermatome; transcriptomics Significance StatementGrowth of noninjured axons in the adult nervous system contributes to adaptive and maladaptive plasticity, and dysfunction of this process may contribute to neurologic pathologies. Functional screening of genes regulated during growth of noninjured axons revealed CD2AP as a positive regulator of axon outgrowth. A novel association of CD2AP with TrkA and p85 suggests a distinct intracellular signaling pathway regulating growth of noninjured axons. This may also represent a novel mechanism of generating specificity in multifunctional NGF signaling. Divergent regulation of CD2AP in different axon growth conditions suggests that separate mechanisms exist for different modes of axon growth. CD2AP is the first signaling molecule associated with adult sensory axonal collateral sprouting, and this association may offer new insights for NGF/TrkA-related Alzheimer's disease mechanisms.

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“…In this context, the large NGF-increase after operative procedures could signal neurologic impairment or the beginning of cerebral deterioration. This explanation is supported by studies that have postulated increased levels of NGF to be associated with central nervous injury as stroke [23], multiple sclerosis [33] traumatic head injury [34], Alzheimer's disease [24] and epileptic seizures [35]. Increased serum NGF could hereby serve as a marker for arising neurologic complications, playing a role in an intrinsic attempt to compensate nervous injury.…”

Section: Discussionmentioning

confidence: 87%

Reduced NGF-Serum Concentrations in Coronary Artery Disease Patients Increase after Coronary Artery Bypass Grafting

Köhler¹

2012

J Clin Exp Cardiolog

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Background: Coronary Artery Disease (CAD) is the leading cause of death worldwide, but neurological deficits are the most devastating complications of its treatment, Coronary Artery Bypass Surgery (CABG). As Nerve Growth Factor (NGF) has been implicated in the modulation of inflammatory and fibroproliferative mechanisms leading to atherosclerosis as well as in neuroprotection and survival of neurons, the time course of NGF serum concentrations during CABG has been studied. Methods:Twenty-six male patients were scheduled for coronary artery bypass grafting and NGF levels have been measured 1 hour before the operation started and 2, 5 and 120 hours postoperatively. Pre-operation values of NGFs were compared to healthy controls. Results:We found significantly lower NGF serum concentrations in coronary artery disease patients (n=26, age: 68.8 ± 5.5 years, mean NGF: 13.04 ± 32.1 pg/ml) as compared to age-matched healthy controls (n=20, age: 64.35 ± 4.15, mean NGF: 29.54 ± 24.23 pg/ml). A significant increase of NGF was found 120 hours after operation (Z=3.26, p=0.001).Conclusion: NGF seems to be decreased in coronary artery disease and is increased by operative coronary revascularization procedures. Changes occurring during cardiac surgery may indicate beneficial regenerative processes but may also implicate neuronal alterations induced by operative procedures.

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Nerve Growth Factor Accelerates Seizure Development, Enhances Mossy Fiber Sprouting, and Attenuates Seizure-Induced Decreases in Neuronal Density in the Kindling Model of Epilepsy

Cited by 116 publications

References 62 publications

A role for Src kinase in spontaneous epileptiform activity in the CA3 region of the hippocampus

A role for Src kinase in spontaneous epileptiform activity in the CA3 region of the hippocampus

The Adaptor Protein CD2AP Is a Coordinator of Neurotrophin Signaling-Mediated Axon Arbor Plasticity

Reduced NGF-Serum Concentrations in Coronary Artery Disease Patients Increase after Coronary Artery Bypass Grafting

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