Timely regulated sorting from early to late endosomes is required to maintain cerebellar long-term depression

Kim, Taegon; Yamamoto, Yukio; Tanaka-Yamamoto, Keiko

doi:10.1038/s41467-017-00518-3

Cited by 16 publications

(29 citation statements)

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“…The deterministic model that we previously created (Kim et al, 2017) contained all the essential compartments to describe endosomal trafficking as well as lateral diffusion on the synaptic and extrasynaptic surface. The stochastic model in this present study also utilized the same essential compartments (Figure 1A), but the detailed structures of two compartments were modified.…”

Section: Methodsmentioning

confidence: 99%

“…As briefly mentioned above, in our model, Rab5-positive EE sites represent the vacuolar portion of the EE. According to the experimental results (Rink et al, 2005; Poteryaev et al, 2010) and modeling study (Del Conte-Zerial et al, 2008), the kinetics of Rab5 accumulation appear to follow the kinetics of autocatalysis, which was introduced by the simplified equation in the previous deterministic model (Kim et al, 2017). In the current model, Rab5 accumulation was simulated by adjusting the lifetime of Rab5 in an EE site ( τ Rab5 ) to be similar to the kinetics of formation of the vacuolar portion in the previous model, using the equation shown below.…”

Section: Methodsmentioning

confidence: 99%

“…On the other hand, previous studies indicated that endosomal trafficking in the postsynaptic cytosol is necessary for long-term plasticity (Ehlers, 2000; Gerges et al, 2004; Brown et al, 2005, 2007; Petrini et al, 2009; Fernández-Monreal et al, 2012; Matsuda et al, 2013; Bacaj et al, 2015). In particular, our recent work on cerebellar LTD demonstrated that another switch working after the positive feedback molecular switch loses its effect, is likely to be a member of the endosomal trafficking pathway (Kim et al, 2017). The stimulation triggering LTD at synapses between parallel fibers (PFs) and Purkinje cells (PCs) activates a positive feedback loop of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK; Tanaka and Augustine, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Postsynaptic Stability and Variability Described by a Stochastic Model of Endosomal Trafficking

Kim

Tanaka-Yamamoto

2019

Front. Cell. Neurosci.

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Neurons undergo dynamic processes of constitutive AMPA-type glutamate receptor (AMPAR) trafficking, such as the insertion and internalization of AMPARs by exocytosis and endocytosis, while stably maintaining synaptic efficacy. Studies using advanced imaging techniques have suggested that the frequency of these constitutive trafficking processes, as well as the number of AMPARs that are involved in a particular event highly fluctuate. In addition, mechanisms that trigger some forms of synaptic plasticity have been shown to include not only these processes but also additional fluctuating processes, such as the sorting of AMPARs to late endosomes (LEs). Thus, the regulation of postsynaptic AMPARs by the endosomal trafficking system appears to have superficially conflicting properties between the stability or organized control of plasticity and highly fluctuating or stochastic processes. However, it is not clear how the endosomal trafficking system reconciles and utilizes such conflicting properties. Although deterministic models have been effective to describe the stable maintenance of synaptic AMPAR numbers by constitutive recycling, as well as the involvement of endosomal trafficking in synaptic plasticity, they do not take stochasticity into account. In this study, we introduced the stochasticity into the model of each crucial machinery of the endosomal trafficking system. The specific questions we solved by our improved model are whether stability is accomplished even with a combination of fluctuating processes, and how overall variability occurs while controlling long-term synaptic depression (LTD). Our new stochastic model indeed demonstrated the stable regulation of postsynaptic AMPAR numbers at the basal state and during LTD maintenance, despite fast fluctuations in AMPAR numbers as well as high variability in the time course and amounts of LTD. In addition, our analysis suggested that the high variability arising from this stochasticity is beneficial for reproducing the relatively constant timing of LE sorting for LTD. We therefore propose that the coexistence of stability and stochasticity in the endosomal trafficking system is suitable for stable synaptic transmission and the reliable induction of synaptic plasticity, with variable properties that have been observed experimentally.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Postsynaptic Stability and Variability Described by a Stochastic Model of Endosomal Trafficking

Kim

Tanaka-Yamamoto

2019

Front. Cell. Neurosci.

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“…In a stimulus dependent manner, AMPA and kainate type glutamate receptors are endocytosed, ubiquitinated and subjected to endosomal sorting processes that either direct the internalized receptors towards recycling endosomes for plasma membrane reinsertion or to lysosomes for degradation (78)(79)(80)(81)(82). This endosomal trafficking leading to lysosomal destruction of AMPA receptors is physiologically important for AMPA receptor down regulation in the contexts of plasticity and pathology (83)(84)(85). In parallel, evidence has also been presented in support of a role for autophagy in the down-regulation of AMPA receptors in long term depression (86).…”

Section: Dendritic Lysosomes and Synaptic Plasticitymentioning

confidence: 99%

Neuronal lysosomes

Ferguson

2019

Neuroscience Letters

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Lysosomes support diverse cellular functions by acting as sites of macromolecule degradation and nutrient recycling. The degradative abilities of lysosomes are conferred by a lumen that is characterized by an acidic pH and which contains numerous hydrolases that support the breakdown of major cellular macromolecules to yield cellular building blocks (amino acids, nucleic acids, sugars, lipids and metals) that are transported into the cytoplasm for their re-use. In addition to these important hydrolytic and recycling functions, lysosomes also serve as a signaling platform that integrates nutrient and metabolic cues to control signaling via the mTORC1 pathway. Due to their extreme longevity, polarity, demands of neurotransmission and metabolic activity, neurons are particularly sensitive to perturbations in lysosome function. The dependence of neurons on optimal lysosome function is highlighted by insights from human genetics that link lysosome dysfunction to a wide range of both rare and common neurological diseases. How then is lysosome function adapted to the unique demands of neurons? This review will focus on the roles played by lysosomes in distinct neuronal sub-compartments, the regulation of neuronal lysosome sub-cellular localization and the implications of such neuronal lysosome regulation for both physiology and disease.

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“…We assumed that maintenance of the receptor density at the activated synapse occurred only due to de novo synthesized proteins, which is a clear simplification of the model [9,10,14]. Recycling of receptor proteins at the synapse is implemented through the mechanisms of their endo-and exocytosis and is closely related to the ubiquitin-dependent protein degradation during formation of synaptic plasticity [15,16]. That suggests the influence of the recycling pool of receptor proteins at the activated synapse on the dynamics of their de novo synthesis.…”

Section: Introductionmentioning

confidence: 99%

On the dynamical aspects of local translation at the activated synapse

2020

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Background The key role in the dynamic regulation of synaptic protein turnover belongs to the Fragile X Mental Retardation Protein, which regulates the efficiency of dendritic mRNA translation in response to stimulation of metabotropic glutamate receptors at excitatory synapses of the hippocampal pyramidal cells. Its activity is regulated via positive and negative regulatory loops that function in different time ranges, which is an absolute factor for the formation of chaotic regimes that lead to disrupted proteome stability. The indicated condition may cause a number of neuropsychiatric diseases, including autism and epilepsy. The present study is devoted to a theoretical analysis of the local translation system dynamic properties and identification of parameters affecting the chaotic potential of the system. Results A mathematical model that describes the maintenance of a specific pool of active receptors on the postsynaptic membrane via two mechanisms – de novo synthesis of receptor proteins and restoration of protein function during the recycling process – has been developed. Analysis of the model revealed that an increase in the values of the parameters describing the impact of protein recycling on the maintenance of a pool of active receptors in the membrane, duration of the signal transduction via the mammalian target of rapamycin pathway, influence of receptors on the translation activation, as well as reduction of the rate of synthesis and integration of de novo synthesized proteins into the postsynaptic membrane – contribute to the reduced complexity of the local translation system dynamic state. Formation of these patterns significantly depends on the complexity and non-linearity of the mechanisms of exposure of de novo synthesized receptors to the postsynaptic membrane, the correct evaluation of which is currently problematic. Conclusions The model predicts that an increase of “receptor recycling” and reduction of the rate of synthesis and integration of de novo synthesized proteins into the postsynaptic membrane contribute to the reduced complexity of the local translation system dynamic state. Herewith, stable stationary states occur much less frequently than cyclic states. It is possible that cyclical nature of functioning of the local translation system is its “normal” dynamic state.

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Timely regulated sorting from early to late endosomes is required to maintain cerebellar long-term depression

Cited by 16 publications

References 58 publications

Postsynaptic Stability and Variability Described by a Stochastic Model of Endosomal Trafficking

Postsynaptic Stability and Variability Described by a Stochastic Model of Endosomal Trafficking

Neuronal lysosomes

On the dynamical aspects of local translation at the activated synapse

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