The kinase activity of EphA4 mediates homeostatic scaling-down of synaptic strength via activation of Cdk5

Peng, Yi-Rong; Hou, Zai-Hua; Yu, Xiang

doi:10.1016/j.neuropharm.2012.10.012

Cited by 17 publications

(18 citation statements)

References 55 publications

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“…7H), consistent with previous reports (Seeburg et al 2008;Kim and Ryan 2010;Mitra et al 2011). Our data suggests that Cdk5 can rapidly depress NMDA and AMPA responses, using a transcription-and translation-independent mechanism, and that Cdk5 depresses transmission via a kinase mechanism (Chergui et al 2004;Peng et al 2013). Interestingly, Cdk5 reacts quickly (within ∼15 min) in response to altered synaptic transmission.…”

Section: Physiological Cdk5 Signalingsupporting

confidence: 91%

“…Although subsequent studies have provided more supports for the involvement of Cdk5 signaling at synapses, the exact function of Cdk5 remains elusive. For example, some studies showed that Cdk5 suppresses the N-methyl--aspartate (NMDA)-sensitive glutamatergic receptor (-R)-mediated synaptic transmission (Hawasli et al 2007;Plattner et al 2014), whereas the others reported that Cdk5 signaled a rapid depression of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-R-mediated transmission with a time course of less than an hour, via a presumably rapid kinase mechanism (Chergui et al 2004;Peng et al 2013). Moreover, several laboratories independently demonstrated that Cdk5 regulated AMPA-R-mediated transmission using a homeostasis-like mechanism (Seeburg et al 2008;Kim and Ryan 2010;Mitra et al 2011), which is expected to take >2-12 h to occur (Turrigiano 2008).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cdk5 is a New Rapid Synaptic Homeostasis Regulator Capable of Initiating the Early Alzheimer-Like Pathology

Sheng¹,

Zhang²,

Su³

et al. 2015

Cereb. Cortex

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Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase implicated in synaptic plasticity, behavior, and cognition, yet its synaptic function remains poorly understood. Here, we report that physiological Cdk5 signaling in rat hippocampal CA1 neurons regulates homeostatic synaptic transmission using an unexpectedly rapid mechanism that is different from all known slow homeostatic regulators, such as beta amyloid (Aβ) and activity-regulated cytoskeleton-associated protein (Arc, aka Arg3.1). Interestingly, overproduction of the potent Cdk5 activator p25 reduces synapse density, and dynamically regulates synaptic size by suppressing or enhancing Aβ/Arc production. Moreover, chronic overproduction of p25, seen in Alzheimer's patients, induces initially concurrent reduction in synapse density and increase in synaptic size characteristic of the early Alzheimer-like pathology, and later persistent synapse elimination in intact brains. These results identify Cdk5 as the regulator of a novel rapid form of homeostasis at central synapses and p25 as the first molecule capable of initiating the early Alzheimer's synaptic pathology.

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Section: Physiological Cdk5 Signalingsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Cdk5 is a New Rapid Synaptic Homeostasis Regulator Capable of Initiating the Early Alzheimer-Like Pathology

Sheng¹,

Zhang²,

Su³

et al. 2015

Cereb. Cortex

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“…Cdk5 is able to determinate the size recycling synaptic vesicles pool [82,83] and modulate the exocytosis of synaptic vesicle [84]. In parallel, the kinase EphA4, upon activating Cdk5 activity, has been proved to reconcile the scaling-down of excitatory synaptic strength [85]. Furthermore, silencing of Cdk5 turns the resting synaptic vesicle pool into the recycling synaptic vesicle pool [82].…”

Section: Cdk5 Modulates Synaptic Plasticitymentioning

confidence: 99%

“…Other studies have reported that Cdk5 modulates spine formation and morphology through regulating many relevant substrates activity, such as, Pctaire1, Rho GTPase Rac1 effector PAK1, Rho GTPase Rac1 modulators GEF RasGRF2 and GAP achimaerin. Cdk5 is connected with EphA4-mediated spine remodeling by phosphorylating the ephexin 1 pathway [85]. Cdk5 also has a negative role in regulating the expression of transcription factor MEF2 by phosphorylating residue Ser-444, which leads to an increase spine density in response to chronic cocaine treatment [100,101].…”

Section: Cdk5 Modulates Synaptic Plasticitymentioning

confidence: 99%

The Role of Cdk5 in Alzheimer’s Disease

et al. 2015

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Alzheimer's disease (AD) is known as the most fatal chronic neurodegenerative disease in adults along with progressive loss of memory and other cognitive function disorders. Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (Cdks), is reported to intimately associate with the process of the pathogenesis of AD. Cdk5 is of vital importance in the development of CNS and neuron movements such as neuronal migration and differentiation, synaptic functions, and memory consolidation. However, when neurons suffer from pathological stimuli, Cdk5 activity becomes hyperactive and causes aberrant hyperphosphorylation of various substrates of Cdk5 like amyloid precursor protein (APP), tau and neurofilament, resulting in neurodegenerative diseases like AD. Deregulation of Cdk5 contributes to an array of pathological events in AD, ranging from formation of senile plaques and neurofibrillary tangles, synaptic damage, mitochondrial dysfunction to cell cycle reactivation as well as neuronal cell apoptosis. More importantly, an inhibition of Cdk5 activity with inhibitors such as RNA inference (RNAi) could protect from memory decline and neuronal cell loss through suppressing β-amyloid (Aβ)-induced neurotoxicity and tauopathies. This review will briefly describe the above-mentioned possible roles of Cdk5 in the physiological and pathological mechanisms of AD, further discussing recent advances and challenges in Cdk5 as a therapeutic target.

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“…The activation of cyclin-dependent kinase 5 (Cdk5) and ephexin1 by ephrin-A1 promotes EphA4-dependent spine retraction, followed by a scaling-down of excitatory synaptic strength (Fu et al, 2007; Peng et al, 2013). EphA4 also inhibits integrin signaling pathways (Bourgin et al, 2007), and EphA4 activation by ephrin-A3 reduces tyrosine phosphorylation of the scaffolding protein Crk-associated substrate (Cas), the tyrosine kinase focal adhesion kinase (FAK), and proline-rich tyrosine kinase 2 (Pyk2) while down-regulating the association of Cas with the Src family kinase Fyn and the adaptor Crk.…”

Section: Cams: Bridges Across the Synaptic Cleftmentioning

confidence: 99%

Intercellular protein–protein interactions at synapses

2014

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Chemical synapses are asymmetric intercellular junctions through which neurons send nerve impulses to communicate with other neurons or excitable cells. The appropriate formation of synapses, both spatially and temporally, is essential for brain function and depends on the intercellular protein-protein interactions of cell adhesion molecules (CAMs) at synaptic clefts. The CAM proteins link pre- and post-synaptic sites, and play essential roles in promoting synapse formation and maturation, maintaining synapse number and type, accumulating neurotransmitter receptors and ion channels, controlling neuronal differentiation, and even regulating synaptic plasticity directly. Alteration of the interactions of CAMs leads to structural and functional impairments, which results in many neurological disorders, such as autism, Alzheimer’s disease and schizophrenia. Therefore, it is crucial to understand the functions of CAMs during development and in the mature neural system, as well as in the pathogenesis of some neurological disorders. Here, we review the function of the major classes of CAMs, and how dysfunction of CAMs relates to several neurological disorders.

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The kinase activity of EphA4 mediates homeostatic scaling-down of synaptic strength via activation of Cdk5

Cited by 17 publications

References 55 publications

Cdk5 is a New Rapid Synaptic Homeostasis Regulator Capable of Initiating the Early Alzheimer-Like Pathology

Cdk5 is a New Rapid Synaptic Homeostasis Regulator Capable of Initiating the Early Alzheimer-Like Pathology

The Role of Cdk5 in Alzheimer’s Disease

Intercellular protein–protein interactions at synapses

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