Opposing Action of Nuclear Factor κB and Polo-like Kinases Determines a Homeostatic End Point for Excitatory Synaptic Adaptation

Mihalas, Anca B.; Araki, Yasuhisa; Huganir, Richard L.; Meffert, Mollie K.

doi:10.1523/jneurosci.2131-13.2013

Cited by 23 publications

(23 citation statements)

References 41 publications

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“…mRNA expression rates depend on transcription factor activation. Many important transcription factors such as CREB are known to be Ca 2+ dependent or dependent on other Ca 2+ -sensing enzymes (Finkbeiner and Greenberg 1998; Mermelstein et al, 2000; Mihalas et al, 2013; Wheeler et al, 2012). Furthermore, transcriptional changes in ion channel genes occur in response to activity perturbations (Kim et al, 2010) and may underlie homeostatic regulation of network activity (Thoby-Brisson and Simmers 2000).…”

Section: Resultsmentioning

confidence: 99%

Cell Types, Network Homeostasis, and Pathological Compensation from a Biologically Plausible Ion Channel Expression Model

O’Leary

Williams

Franci

et al. 2014

Neuron

278

369

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SUMMARY How do neurons develop, control, and maintain their electrical signaling properties in spite of ongoing protein turnover and perturbations to activity? From generic assumptions about the molecular biology underlying channel expression, we derive a simple model and show how it encodes an “activity set point” in single neurons. The model generates diverse self-regulating cell types and relates correlations in conductance expression observed in vivo to underlying channel expression rates. Synaptic as well as intrinsic conductances can be regulated to make a self-assembling central pattern generator network; thus, network-level homeostasis can emerge from cell-autonomous regulation rules. Finally, we demonstrate that the outcome of homeostatic regulation depends on the complement of ion channels expressed in cells: in some cases, loss of specific ion channels can be compensated; in others, the homeostatic mechanism itself causes pathological loss of function.

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Section: Resultsmentioning

confidence: 99%

Cell Types, Network Homeostasis, and Pathological Compensation from a Biologically Plausible Ion Channel Expression Model

O’Leary

Williams

Franci

et al. 2014

Neuron

278

369

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“…; Mihalas et al . ). Through the inhibition of inhibitory input in the cultures, the overall neuronal excitability is elevated, which ultimately triggers a homeostatic mechanism to restore the baseline activity (Frischknecht et al .…”

Section: Resultsmentioning

confidence: 97%

The tumor suppressor p53 guides GluA1 homeostasis through Nedd4‐2 during chronic elevation of neuronal activity

Jewett

Zhu

Tsai

2015

Journal of Neurochemistry

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Chronic activity perturbation in neurons can trigger homeostatic mechanisms to restore the baseline function. Although the importance and dysregulation of neuronal activity homeostasis has been implicated in neurological disorders such as epilepsy, the complete signaling by which chronic changes in neuronal activity initiate the homeostatic mechanisms is unclear. We report here that the tumor suppressor p53 and its signaling are involved in neuronal activity homeostasis. Upon chronic elevation of neuronal activity in primary cortical neuron cultures, the ubiquitin E3 ligase, murine double minute-2 (Mdm2), is phosphorylated by the kinase Akt. Phosphorylated Mdm2 triggers the degradation of p53 and subsequent induction of a p53 target gene, neural precursor cell expressed developmentally down-regulated gene 4-like (Nedd4-2). Nedd4-2 encodes another ubiquitin E3 ligase. We identified glutamate receptor subunit 1 (GluA1), subunit of alphaamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors as a novel substrate of Nedd4-2. The regulation of GluA1 level is known to be crucial for neuronal activity homeostasis. We confirmed that, by pharmacologically inhibiting Mdm2-mediated p53 degradation or genetically reducing Nedd4-2 in a mouse model, the GluA1 ubiquitination and down-regulation induced by chronically elevated neuronal activity are both attenuated. Our findings demonstrate the first direct function of p53 in neuronal homeostasis and elucidate a new mechanism by which cortical neurons respond to chronic activity perturbation. Keywords: GluA1, Mdm2, Nedd4-2, neuronal activity, p53, ubiquitination. The ubiquitin E3 ligase, murine double minute-2 (Mdm2), and its substrate p53, are well known in the regulation of apoptosis (Dornan et al. 2004), cell cycle control (Goldberg et al. 2002;Zhang and Zhang 2008), and cellular stress Received May 3, 2015; revised manuscript received July 9, 2015; accepted July 27, 2015.Address correspondence and reprint requests to Nien-Pei Tsai, PhD, 407 South Goodwin Ave., Urbana, IL 61801, USA. E-mail:nptsai@illi nois.eduAbbreviations used: AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; DMSO, dimethyl sulfoxide; GluA1, glutamate receptor subunit 1; GluA2, glutamate receptor subunit 2; HA, hemagglutinin; HEK, human embryonic kidney; Nedd4-1, neural precursor cell expressed developmentally down-regulated protein 4; Nedd4-2, neural precursor cell expressed developmentally down-regulated gene 4-like. 226

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“…Expression of polo-like kinases (PLKs), which are involved in activity-dependent synaptic remodeling via their ability to regulate dendritic spine retraction, can activate NF-κB in hippocampal neurons through the canonical pathway (e.g., involving IκB degradation induced by IKK activation; Mihalas et al, 2013). In p65-deficient cultured neurons, activation of PLKs resulted in significantly greater dendritic spine and glutamate receptor loss relative to activation of PLKs in control neurons, suggesting that NF-κB serves as a counterbalance to prevent overshooting of dendritic spine loss exerted by PLKs in response to high excitatory activity (Mihalas et al, 2013). …”

Section: Activators Of Nf-κb In Neuronsmentioning

confidence: 99%

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

Snow

Albensi

2016

Front. Mol. Neurosci.

136

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Although, better known for its role in inflammation, the transcription factor nuclear factor kappa B (NF-κB) has more recently been implicated in synaptic plasticity, learning, and memory. This has been, in part, to the discovery of its localization not just in glia, cells that are integral to mediating the inflammatory process in the brain, but also neurons. Several effectors of neuronal NF-κB have been identified, including calcium, inflammatory cytokines (i.e., tumor necrosis factor alpha), and the induction of experimental paradigms thought to reflect learning and memory at the cellular level (i.e., long-term potentiation). NF-κB is also activated after learning and memory formation in vivo. In turn, activation of NF-κB can elicit either suppression or activation of other genes. Studies are only beginning to elucidate the multitude of neuronal gene targets of NF-κB in the normal brain, but research to date has confirmed targets involved in a wide array of cellular processes, including cell signaling and growth, neurotransmission, redox signaling, and gene regulation. Further, several lines of research confirm dysregulation of NF-κB in Alzheimer's disease (AD), a disorder characterized clinically by a profound deficit in the ability to form new memories. AD-related neuropathology includes the characteristic amyloid beta plaque formation and neurofibrillary tangles. Although, such neuropathological findings have been hypothesized to contribute to memory deficits in AD, research has identified perturbations at the cellular and synaptic level that occur even prior to more gross pathologies, including transcriptional dysregulation. Indeed, synaptic disturbances appear to be a significant correlate of cognitive deficits in AD. Given the more recently identified role for NF-κB in memory and synaptic transmission in the normal brain, the expansive network of gene targets of NF-κB, and its dysregulation in AD, a thorough understanding of NF-κB-related signaling in AD is warranted and may have important implications for uncovering treatments for the disease. This review aims to provide a comprehensive view of our current understanding of the gene targets of this transcription factor in neurons in the intact brain and provide an overview of studies investigating NF-κB signaling, including its downstream targets, in the AD brain as a means of uncovering the basic physiological mechanisms by which memory becomes fragile in the disease.

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Opposing Action of Nuclear Factor κB and Polo-like Kinases Determines a Homeostatic End Point for Excitatory Synaptic Adaptation

Cited by 23 publications

References 41 publications

Cell Types, Network Homeostasis, and Pathological Compensation from a Biologically Plausible Ion Channel Expression Model

Cell Types, Network Homeostasis, and Pathological Compensation from a Biologically Plausible Ion Channel Expression Model

The tumor suppressor p53 guides GluA1 homeostasis through Nedd4‐2 during chronic elevation of neuronal activity

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

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