The Receptor Tyrosine Kinase EphB2 Regulates NMDA-Dependent Synaptic Function

Henderson, Jeffrey T.; Georgiou, John; Jia, Zhenping; Robertson, John C.; Elowe, Sabine; Roder, John; Pawson, Tony

doi:10.1016/s0896-6273(01)00553-0

Cited by 288 publications

(223 citation statements)

References 46 publications

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“…S3A). EphA4 is involved in the regulation of synaptic plasticity (Murai et al ., 2003; Filosa et al ., 2009), and EphB2 controls both spine formation (Penzes et al ., 2003) and synaptic plasticity (Grunwald et al ., 2001, 2004; Henderson et al ., 2001; Margolis et al ., 2010). Thus, our results suggest that the age‐upregulated miRNAs downregulate the Eph/ephrin signaling pathway involved in synaptic function and plasticity.…”

Section: Resultsmentioning

confidence: 99%

miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

et al. 2016

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SummaryHippocampal synaptic function and plasticity deteriorate with age, often resulting in learning and memory deficits. As MicroRNAs (miRNAs) are important regulators of neuronal protein expression, we examined whether miRNAs may contribute to this age‐associated decline in hippocampal function. We first compared the small RNA transcriptome of hippocampal tissues from young and old mice. Among 269 hippocampal miRNAs, 80 were differentially expressed (≥ twofold) among the age groups. We focused on 36 miRNAs upregulated in the old mice compared with those in the young mice. The potential targets of these 36 miRNAs included 11 critical Eph/Ephrin synaptic signaling components. The expression levels of several genes in the Eph/Ephrin pathway, including EphB2, were significantly downregulated in the aged hippocampus. EphB2 is a known regulator of synaptic plasticity in hippocampal neurons, in part by regulating the surface expression of the NMDA receptor NR1 subunit. We found that EphB2 is a direct target of miR‐204 among miRNAs that were upregulated with age. The transfection of primary hippocampal neurons with a miR‐204 mimic suppressed both EphB2 mRNA and protein expression and reduced the surface expression of NR1. Transfection of miR‐204 also decreased the total expression of NR1. miR‐204 induces senescence‐like phenotype in fully matured neurons as evidenced by an increase in p16‐positive cells. We suggest that aging is accompanied by the upregulation of miR‐204 in the hippocampus, which downregulates EphB2 and results in reduced surface and total NR1 expression. This mechanism may contribute to age‐associated decline in hippocampal synaptic plasticity and the related cognitive functions.

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Section: Resultsmentioning

confidence: 99%

miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

et al. 2016

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“…Targeted deletion of EphB2 in rodents has revealed that EphB2 plays a critical role in regulating N-methyl-D-aspartate-receptor calcium signaling and in the establishment of LTP, particularly in the hippocampal perforant path [96][97][98]. More recently, compelling evidence has shown EphB2 to be directly implicated in dendritic spine formation during development through the temporally precise inhibition of RhoA signaling [99].…”

Section: Ephb2/ephexin-5mentioning

confidence: 99%

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

Lefort

2015

Neurotherapeutics

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Alzheimer's disease (AD) is a monumental public health crisis with no effective cure or treatment. To date, therapeutic strategies have focused almost exclusively on upstream signaling events in the disease, namely on β-amyloid and amyloid precursor protein processing, and have, unfortunately, yielded few, if any, promising results. An alternative approach may be to target signaling events downstream of β-amyloid and even tau. However, with so many pathways already linked to the disease, understanding which ones are "drivers" versus "passengers" in the pathogenesis of the disease remains a tremendous challenge. Given the critical roles of Rho-guanosine triphosphatases (GTPases) in regulating the actin cytoskeleton and spine dynamics, and the strong association between spine abnormalities and cognition, it is not surprising that mutations in a number of genes involved in RhoGTPase signaling have been implicated in several brain disorders, including schizophrenia and autism. And now, there is mounting literature implicating Rho-GTPase signaling in AD pathogenesis as well. Here, I review this evidence, with a particular emphasis on the regulators of Rho-GTPase signaling, namely guanine nucleotide exchange factors and GTPaseactivating proteins. Several of these have been linked to various aspects of AD, and each offers a novel potential therapeutic target for AD.

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“…On the other hand several studies have implied axon guidance cues in synaptic plasticity and learning (Gerlai et al, 2001). EphB2 regulates NMDA-dependent synaptic function and is up regulated in hippocampal pyramidal neurons by stimuli known to induce changes in synaptic structure (Henderson et al, 2001). Mice lacking EphB2 have normal hippocampal synapse morphology, but display defects in synaptic plasticity (Grunwald et al, 2001), long-term potentiation (LTP) is impaired, and two forms of synaptic depression are completely extinguished (Gosh, 2002, Grunwald et al, 2001, Henderson et al, 2001.…”

Section: Drug-induced Expression Changes Of Axon Guidance Cues May Bementioning

confidence: 99%

“…EphB2 regulates NMDA-dependent synaptic function and is up regulated in hippocampal pyramidal neurons by stimuli known to induce changes in synaptic structure (Henderson et al, 2001). Mice lacking EphB2 have normal hippocampal synapse morphology, but display defects in synaptic plasticity (Grunwald et al, 2001), long-term potentiation (LTP) is impaired, and two forms of synaptic depression are completely extinguished (Gosh, 2002, Grunwald et al, 2001, Henderson et al, 2001. Conditional ablation of Ephrin-B2 and Ephrin-B3, or of EphA4, a high-affinity receptor for these ligands, causes comparable defects in LTP (Grunwald et al, 2004).…”

Section: Drug-induced Expression Changes Of Axon Guidance Cues May Bementioning

confidence: 99%

“…Semaphorins might significantly contribute to the maintenance and stability of neuronal networks and play important roles in the regeneration, or failure thereof, of neuronal connections (De Wit and Verhaagen, 2003). Eph receptors are involved in synaptic plasticity (Grünwald et al, 2001, Henderson et al, 2001) and several Eph molecules are upregulated after injury (Willson et al, 2002, Battaglia et al, 2003, Knöll et al, 2001). Nevertheless little is known about cell surface molecules involved in neuroadaptations after drug intake.…”

Section: Introductionmentioning

confidence: 99%

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Cocaine-induced expression changes of axon guidance molecules in the adult rat brain

Bahí

Dreyer

2005

Molecular and Cellular Neuroscience

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Administration of drugs of abuse induces strong molecular adaptations and plasticity within the mesolimbic dopamine (DA) system, a pathway essential for reward-seeking behavior. Little is known about the specific targets involved in this neuroadaptation process, but there are indications that cocaine and other drugs of abuse share the ability to alter the morphology of neuronal dendrites and spines, the primary site of excitatory synapses in the brain. Axon guidance molecules, the very molecular cues that regulate the formation of axon-target connections during development, may mediate these alterations. To test this hypothesis, we investigated mRNA expression changes of 39 axon guidance molecules, including 17 Semaphorins, 12 Ephs, 8 Ephrins and 2 neuropilins in the mesolimbic dopamine system of cocaine-treated animals under different paradigms by mean of DNA-Microarray and quantitative real-time PCR. In all cases, strong changes in gene expression are observed, yielding to up or down-regulation of these axon guidance molecules. Our data suggest that cocaine treatment induces activation of a complex program of synaptic rearrangements, which may partly recapitulate the plastic changes occurring during development, and may underlie the important neuroplastic adaptations that occur in the reward-and memory-related brain centers following drug action. We conclude that in some brain regions, exposure to psychomotor-stimulant drugs produce expression changes in axon guidance molecules, which may contribute to cognitive deficits associated with drug abuse.2

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The Receptor Tyrosine Kinase EphB2 Regulates NMDA-Dependent Synaptic Function

Cited by 288 publications

References 46 publications

miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

Cocaine-induced expression changes of axon guidance molecules in the adult rat brain

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