Neuroimmune Modulation of Synaptic Function

Pribiag, Horia; Stellwagen, David

doi:10.1007/978-1-4614-4729-0_3

Cited by 3 publications

(3 citation statements)

References 209 publications

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“…Extracellular diffusion of glutamate can lead to the loss of synaptic fidelity, decreased specificity of neurotransmission, and lead to 'noisy', non-specific, and disruptive neural activity experienced by patients as cognitive and affective symptoms (Dorsett et al, 2016). Although precise data are lacking, we speculate that inflammatory activation in mood disorders might lead to increased AMPA activity during early phases followed by desensitization and decreased AMPA activity in later stages resulting in synaptic depression, decreased transmission efficiency, and impaired synaptic plasticity (Choquet and Triller, 2013;Popoli et al, 2012;Pribiag and Stellwagen, 2014;Pribiag and Stellwagen, 2013).…”

Section: Conceptual Convergence: a Working Modelmentioning

confidence: 91%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

414

299

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Increasing data indicate that inflammation and alterations in glutamate neurotransmission are two novel pathways to pathophysiology in mood disorders. The primary goal of this review is to illustrate how these two pathways may converge at the level of the glia to contribute to neuropsychiatric disease. We propose that a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss. Furthermore, glutamate diffusion outside the synapse can lead to the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction and behavioral pathology. This review examines the fundamental role of glia in the regulation of glutamate, followed by a description of the impact of inflammation on glial glutamate regulation at the cellular, molecular, and metabolic level. In addition, the role of these effects of inflammation on glia and glutamate in mood disorders will be discussed along with their translational implications.

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Section: Conceptual Convergence: a Working Modelmentioning

confidence: 91%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

414

299

View full text Add to dashboard Cite

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“…In the brain, cytokines induce adaptive sickness behaviors, depressive-like behaviors, and disruption of cognitive processes including learning and memory in both rodents and humans ( Dantzer et al., 2008 ; Marin and Kipnis, 2013 ; Raison et al., 2006 ; Yirmiya and Goshen, 2011 ). Interestingly, cytokines such as tumor necrosis factor α (TNFα) ( Santello et al., 2011 ; Stellwagen et al., 2005 ), interleukins (IL) IL-1β ( Huang et al., 2011 ; Viviani et al., 2003 ), IL-6 ( D'Arcangelo et al., 2000 ), and IL-33 ( Nguyen et al., 2020 ), and interferons (IFNs) IFNα, IFNβ, and IFNγ ( Costello and Lynch, 2013 ; Mendoza-Fernández et al., 2000 ; Zhu et al., 2011 ) can modulate synaptic function by altering membrane receptor trafficking, neuronal signaling, extracellular matrix remodeling, and/or neurotransmitter release at both excitatory and inhibitory synapses ( Pribiag and Stellwagen, 2013 ). For example, manipulation of the interleukin family of cytokines can significantly impair in vitro hippocampal long-term potentiation ( Ross et al., 2003 ; Schneider et al., 1998 ) and memory ( Goshen et al., 2007 ) in rodents.…”

Section: Ring the Neuroinflammatory Alarm: Inflammatory Signaling Modulates Cellular Communicationmentioning

confidence: 99%

Three's Company: Neuroimmune activation, sex, and memory at the tripartite synapse

Posillico

2021

Brain, Behavior, & Immunity - Health

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The neuroimmune system is required for normal cognitive functions such as learning and memory in addition to its critical role in detecting and responding to invading pathogens and injury. Understanding the functional convergence of neurons, astrocytes, and microglia at the synapse, particularly in the hippocampus, is key to understanding the nuances of such diverse roles. In the healthy brain, communication between all three cells is important for regulating neuronal activation and synaptic plasticity mechanisms, and during neuroinflammation, the activity and functions of all three cells can produce and be modulated by inflammatory cytokines. An important remaining component to this system is the conclusive evidence of sex differences in hippocampal plasticity mechanisms, hormone modulation of synaptic plasticity, functional properties of hippocampal neurons, and in neuroimmune activation. Sex as a biological variable here is necessary to consider given sex differences in the prevalence of memory-related disorders such as Alzheimer's disease and Post-Traumatic Stress disorder, both of which present with neuroimmune dysregulation. To make meaningful progress towards a deeper understanding of sex biases in memory-related disease prevalence, I propose that the next chapter of psychoneuroimmune research must focus on the signal integration and transduction at the synapse between experience-dependent plasticity mechanisms, neuroimmune activation, and the influence of biological sex.

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“…Neuroinflammation involves increased production and release of microglia and astrocytederived pro-inflammatory cytokines such as TNF-α, IL-6, Il-1β, which ultimately act to increase the ratio of glutamatergic to GABAergic synaptic transmission (Pribiag and Stellwagen, 2013a), which is predicted to increase neural excitability. Conversely, agents that enhance the function of K + channels reduce neuronal excitability.…”

Section: Introductionmentioning

confidence: 99%

Reversal of a Treatment-Resistant, Depression-Related Brain State with the Kv7 Channel Opener Retigabine

et al. 2019

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Neuroinflammation is associated with increased vulnerability to diverse psychiatric conditions, including treatment-resistant major depressive disorder (MDD). Here we assessed whether high fat diet (HFD) induced neuroinflammation may be suitable to model a treatment-resistant depressivelike brain state in mice. Male and female mice were fed a HFD for 18 weeks, followed by quantitation of glucose tolerance, inflammatory markers of brain tissue (TNFα, IL-6, IL-1β, Iba-1), neural excitability in the prelimbic cortex (PLC), as well as assessment of emotional reactivity and hedonic behavior in a battery of behavioral tests. In addition, we assessed the behavioral responsiveness of mice to fluoxetine, desipramine, ketamine, and the Kv7 channel opener and anticonvulsant retigabine. HFD exposure lead to glucose intolerance and neuroinflammation in male mice, with similar but non-significant trends in females. Neuroinflammation of males was associated with anxious-depressive-like behavior and defects in working memory, along with neural hyperexcitability and increased I h currents of pyramidal cells in the PLC. The behavioral changes were largely resistant to chronic treatment with fluoxetine and desipramine, as well as ketamine. By contrast, retigabine (also known as ezogabine) normalized neural excitability and I h currents recorded from slices of HFD-treated animals and significantly ameliorated most of the behavioral impairments, without effects in control diet exposed animals. Thus, treatment resistant depressive-like brain states that are associated with chronic neuroinflammation may involve hyperexcitability of pyramidal neurons and may be effectively treated by retigabine.

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Neuroimmune Modulation of Synaptic Function

Cited by 3 publications

References 209 publications

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Three's Company: Neuroimmune activation, sex, and memory at the tripartite synapse

Reversal of a Treatment-Resistant, Depression-Related Brain State with the Kv7 Channel Opener Retigabine

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