Reduction of increased calcineurin activity rescues impaired homeostatic synaptic plasticity in presenilin 1 M146V mutant

Kim, Seonil; Violette, Caroline; Ziff, Edward B.

doi:10.1016/j.neurobiolaging.2015.09.007

Cited by 39 publications

(59 citation statements)

References 58 publications

(126 reference statements)

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“…Hippocampal PSD fraction preparation from brain was performed as previously described (Kim et al , 2015). Equal amounts of protein were loaded on 10% SDS-PAGE gels and transferred to nitrocellulose or PVDF membranes.…”

Section: Methodsmentioning

confidence: 99%

Lithium increases synaptic GluA2 in hippocampal neurons by elevating the δ-catenin protein

et al. 2017

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Lithium (Li+) is a drug widely employed for treating bipolar disorder, however the mechanism of action is not known. Here we study the effects of Li+ in cultured hippocampal neurons on a synaptic complex consisting of δ-catenin, a protein associated with cadherins whose mutation is linked to autism, and GRIP, an AMPA receptor (AMPAR) scaffolding protein, and the AMPAR subunit, GluA2. We show that Li+ elevates the level of δ-catenin in cultured neurons. δ-catenin binds to the ABP and GRIP proteins, which are synaptic scaffolds for GluA2. We show that Li+ increases the levels of GRIP and GluA2, consistent with Li+-induced elevation of δ-catenin. Using GluA2 mutants, we show that the increase in surface level of GluA2 requires GluA2 interaction with GRIP. The amplitude but not the frequency of mEPSCs was also increased by Li+ in cultured hippocampal neurons, confirming a functional effect and consistent with AMPAR stabilization at synapses. Furthermore, animals fed with Li+ show elevated synaptic levels of δ-catenin, GRIP, and GluA2 in the hippocampus, also consistent with the findings in cultured neurons. This work supports a model in which Li+ stabilizes δ-catenin, thus elevating a complex consisting of δ-catenin, GRIP and AMPARs in synapses of hippocampal neurons. Thus, the work suggests a mechanism by which Li+ can alter brain synaptic function that may be relevant to its pharmacologic action in treatment of neurological disease.

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Section: Methodsmentioning

confidence: 99%

Lithium increases synaptic GluA2 in hippocampal neurons by elevating the δ-catenin protein

et al. 2017

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“…Another study corroborated the deficits in synaptic scaling in hippocampal neurons from Psen1 M146V knock‐in mice, and showed increased calcineurin activity and decreased GluA1 Ser845 phosphorylation in these neurons (Kim et al . ).…”

Section: Homeostatic Synaptic Plasticity and Diseasementioning

confidence: 97%

“…Different lines of evidence indicate that defects in homeostatic plasticity contribute to the pathogenesis of neurological and neuropsychiatric disorders. Alterations in homeostatic signaling have been implicated in intellectual disability and autism spectrum disorders (Soden and Chen 2010;Blackman et al 2012;Qiu et al 2012), schizophrenia (Dickman and Davis 2009), epilepsy (Houweling et al 2005), and in neurodegenerative disorders such as Alzheimer's disease (Pratt et al 2011;Kim et al 2015) and Huntington's disease (Rocher et al 2016). Most of the evidence is related to genes that have been linked to human diseases and that when mutated interfere with homeostatic plasticity [reviewed in (Wondolowski and Dickman 2013)].…”

Section: Homeostatic Synaptic Plasticity and Diseasementioning

confidence: 99%

Mechanisms of homeostatic plasticity in the excitatory synapse

Fernandes

Carvalho

2016

Journal of Neurochemistry

131

115

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Brain development, sensory information processing, and learning and memory processes depend on Hebbian forms of synaptic plasticity, and on the remodeling and pruning of synaptic connections. Neurons in networks implicated in these processes carry out their functions while facing constant perturbation; homeostatic responses are therefore required to maintain neuronal activity within functional ranges for proper brain function. Here, we will review in vitro and in vivo studies demonstrating that several mechanisms underlie homeostatic plasticity of excitatory synapses, and identifying participant molecular players. Emerging evidence suggests a link between disrupted homeostatic synaptic plasticity and neuropsychiatric and neurologic disorders. Keywords: AMPA receptors, experience-dependent plasticity, Hebbian synaptic plasticity, homeostatic synaptic plasticity, synapse, synaptic scaling.This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases". Hebbian and homeostatic synaptic plasticityLearning and memory as well as other forms of human behavior possibly rely on the ability of the mammalian brain to undergo experience-based adaptations in synaptic strength, which becomes stronger or weaker in response to specific patterns of activity. Hebbian synaptic plasticity is the most widely studied form of long-lasting activity-dependent changes in synaptic strength and includes both long-term potentiation (LTP) and its counterpart, long-term depression (LTD). Hebbian forms of plasticity typically function in an input-specific manner, are rapidly induced and long-lasting, and require correlated firing of the pre-and post-synaptic neurons (Malenka and Bear 2004;Luscher and Malenka 2012;Huganir and Nicoll 2013). Because these hallmark features facilitate the reinforcement of precise synaptic connections, which is fundamental for information storage in the brain, these Hebbian mechanisms are thought to be the cellular correlates of learning and memory. However, these same features of Hebbian plasticity pose a stability problem to neural networks. The requirement of correlated activity to reinforce useful pathways in the brain provokes positive feedback loops of activity-dependent changes in synaptic strength. For instance, once LTP is induced, potentiated synapses are more excitable and can undergo further potentiation more easily, entering a cycle that, if unconstrained, eventually drives activity to a state prone to hyperexcitability

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“…Reports by Kim and colleagues from studies performed in presenilin 1-mutant model of AD provided some mechanistic insights into the cognitive decline improvement resulting from reducing calcineurin activation in affected brains [25, 208]. These authors observed that the inhibition of abnormally increased calcineurin activity characteristic of the disease resulted in the stabilization of the phosphorylation of GluA1, a subunit of Ca 2+ -permeable AMPA receptors, and promoted synaptic trafficking of Ca 2+ -permeable AMPA receptors, as well as the resulting improvement in animal cognition [25]. Such improvement resulted at least partly from the restoration of Ca 2+ -permeable AMPA receptor-mediated hippocampal LTP [208].…”

Section: Controversial Roles In Nervous System Diseasesmentioning

confidence: 99%

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

Kipanyula

Kimaro

Etet

2016

Journal of Aging Research

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The ongoing epidemics of metabolic diseases and increase in the older population have increased the incidences of neurodegenerative diseases. Evidence from murine and cell line models has implicated calcineurin-nuclear factor of activated T-lymphocytes (NFAT) signaling pathway, a Ca2+/calmodulin-dependent major proinflammatory pathway, in the pathogenesis of these diseases. Neurotoxins such as amyloid-β, tau protein, and α-synuclein trigger abnormal calcineurin/NFAT signaling activities. Additionally increased activities of endogenous regulators of calcineurin like plasma membrane Ca2+-ATPase (PMCA) and regulator of calcineurin 1 (RCAN1) also cause neuronal and glial loss and related functional alterations, in neurodegenerative diseases, psychotic disorders, epilepsy, and traumatic brain and spinal cord injuries. Treatment with calcineurin/NFAT inhibitors induces some degree of neuroprotection and decreased reactive gliosis in the central and peripheral nervous system. In this paper, we summarize and discuss the current understanding of the roles of calcineurin/NFAT signaling in physiology and pathologies of the adult and developing nervous system, with an emphasis on recent reports and cutting-edge findings. Calcineurin/NFAT signaling is known for its critical roles in the developing and adult nervous system. Its role in physiological and pathological processes is still controversial. However, available data suggest that its beneficial and detrimental effects are context-dependent. In view of recent reports calcineurin/NFAT signaling is likely to serve as a potential therapeutic target for neurodegenerative diseases and conditions. This review further highlights the need to characterize better all factors determining the outcome of calcineurin/NFAT signaling in diseases and the downstream targets mediating the beneficial and detrimental effects.

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Reduction of increased calcineurin activity rescues impaired homeostatic synaptic plasticity in presenilin 1 M146V mutant

Cited by 39 publications

References 58 publications

Lithium increases synaptic GluA2 in hippocampal neurons by elevating the δ-catenin protein

Lithium increases synaptic GluA2 in hippocampal neurons by elevating the δ-catenin protein

Mechanisms of homeostatic plasticity in the excitatory synapse

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

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