IL-6 regulation of synaptic function in the CNS

Gruol, Donna L.

doi:10.1016/j.neuropharm.2014.10.023

Cited by 199 publications

(141 citation statements)

References 176 publications

(235 reference statements)

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“…However, we did not observe any difference in the activation of glial cells in the retina after IL-6 treatment, suggesting a direct effect on ganglion cell activity. In accordance with this idea, it was previously shown that IL-6 decreases N-methyl- D- aspartate activity, weakening synaptic transmission [8,47]. Thus, it is reasonable to propose that IL-6 decreases retinal glutamatergic input to the SC favoring axonal sprouting of the opposite, nontreated eye.…”

Section: Discussionmentioning

confidence: 66%

“…This interleukin increases the survival of retinal ganglion cells (RGCs) in culture [3,4,5] and also in an in vivo model of elevated ocular pressure [6,7]. Other studies have associated IL-6 to synaptic plasticity since endogenous IL-6 inhibition can prolong long-term potentiation and improve memory [8,9,10,11]. Also, IL-6 modulates both excitatory and inhibitory synapses and reduces paired-pulse inhibition [12].…”

Section: Introductionmentioning

confidence: 99%

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Intravitreous Injection of Interleukin-6 Leads to a Sprouting in the Retinotectal Pathway at Different Stages of Development

Menezes

Goulart

Espírito-Santo³

et al. 2016

Neuroimmunomodulation

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Objective: The development of retinotectal pathways form precise topographical maps is usually completed by the third postnatal week. Cytokines participate in the development and plasticity of the nervous system. We have previously shown that in vivo treatment with interleukin 2 disrupts the retinocollicular topographical order in early stages of development. Therefore, we decided to study the effect of a single intravitreous injection of IL-6 upon retinotectal circuitry in neonates and juvenile rats. Materials and Methods: Lister Hooded rats received an intravitreous injection of IL-6 (50 ng/ml) or vehicle (PBS) at either postnatal day (PND)10 or PND30 and the ipsilateral retinotectal pathway was evaluated 4 or 8 days later, respectively. Results: Our data showed that, at different stages of development, a single IL-6 intravitreous treatment did not produce an inflammatory response and increased retinal axon innervation throughout the visual layers of the superior colliculus. Conclusions: Taken together, our data provide the first evidence that a single intravitreous injection with IL-6 leads to sprouting in the subcortical visual connections and suggest that small changes in IL-6 levels might be sufficient to impair the correct neuronal circuitry fine-tuning during brain development.

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Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Intravitreous Injection of Interleukin-6 Leads to a Sprouting in the Retinotectal Pathway at Different Stages of Development

Menezes

Goulart

Espírito-Santo³

et al. 2016

Neuroimmunomodulation

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“…Importantly, the ensuing immunological and metabolic disturbances in the body exert strong feedback effects on cerebral circuits. For example, stress-related increases in levels of cortisol and pro-inflammatory cytokines affect NMDA receptor (NMDAR) function (Nair and Bonneau, 2006; Gruol, 2015; Vezzani and Viviani, 2015). Importantly, NMDAR dependent signaling is thought to be essential for updating and encoding representations of beliefs (Corlett et al, 2010; Vinckier et al, 2016).…”

Section: The Need For a Computational Theory Of Fatiguementioning

confidence: 99%

Allostatic Self-efficacy: A Metacognitive Theory of Dyshomeostasis-Induced Fatigue and Depression

Stephan

Manjaly

Mathys

et al. 2016

Front. Hum. Neurosci.

345

462

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This paper outlines a hierarchical Bayesian framework for interoception, homeostatic/allostatic control, and meta-cognition that connects fatigue and depression to the experience of chronic dyshomeostasis. Specifically, viewing interoception as the inversion of a generative model of viscerosensory inputs allows for a formal definition of dyshomeostasis (as chronically enhanced surprise about bodily signals, or, equivalently, low evidence for the brain's model of bodily states) and allostasis (as a change in prior beliefs or predictions which define setpoints for homeostatic reflex arcs). Critically, we propose that the performance of interoceptive-allostatic circuitry is monitored by a metacognitive layer that updates beliefs about the brain's capacity to successfully regulate bodily states (allostatic self-efficacy). In this framework, fatigue and depression can be understood as sequential responses to the interoceptive experience of dyshomeostasis and the ensuing metacognitive diagnosis of low allostatic self-efficacy. While fatigue might represent an early response with adaptive value (cf. sickness behavior), the experience of chronic dyshomeostasis may trigger a generalized belief of low self-efficacy and lack of control (cf. learned helplessness), resulting in depression. This perspective implies alternative pathophysiological mechanisms that are reflected by differential abnormalities in the effective connectivity of circuits for interoception and allostasis. We discuss suitably extended models of effective connectivity that could distinguish these connectivity patterns in individual patients and may help inform differential diagnosis of fatigue and depression in the future.

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“…The acute IL-6 would presumably activate IL-6Rs on nearby cells and cause functional changes through downstream signaling. IL-6Rs are expressed on several cell types in the hippocampus, including neurons and glia (Gruol, 2014). To assess this possibility we carried out two types of experiment: (a) we measured by ELISA the levels of IL-6 in a separate group of IL-6 tg and non-tg hippocampal slices treated with control saline (ACSF) or 60 mM ethanol for 30 min, and (b) we measured the relative level of activation of downstream signal transduction molecules activated by IL-6.…”

Section: Resultsmentioning

confidence: 99%

Transgenic mice with increased astrocyte expression of IL-6 show altered effects of acute ethanol on synaptic function

et al. 2016

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A growing body of evidence has revealed that resident cells of the central nervous system (CNS), and particularly the glial cells, comprise a neuroimmune system that serves a number of functions in the normal CNS and during adverse conditions. Cells of the neuroimmune system regulate CNS functions through the production of signaling factors, referred to as neuroimmune factors. Recent studies show that ethanol can activate cells of the neuroimmune system, resulting in the elevated production of neuroimmune factors, including the cytokine interleukin-6 (IL-6). Here we analyzed the consequences of this CNS action of ethanol using transgenic mice that express elevated levels of IL-6 through increased astrocyte expression (IL-6-tg) to model the increased IL-6 expression that occurs with ethanol use. Results show that increased IL-6 expression induces neuroadaptive changes that alter the effects of ethanol. In hippocampal slices from non-transgenic (non-tg) littermate control mice, synaptically evoked dendritic field excitatory postsynaptic potential (fEPSP) and somatic population spike (PS) at the Schaffer collateral to CA1 pyramidal neuron synapse were reduced by acute ethanol (20 or 60 mM). In contrast, acute ethanol enhanced the fEPSP and PS in hippocampal slices from IL-6 tg mice. Long-term synaptic plasticity of the fEPSP (i.e., LTP) showed the expected dose-dependent reduction by acute ethanol in non-tg hippocampal slices, whereas LTP in the IL-6 tg hippocampal slices was resistant to this depressive effect of acute ethanol. Consistent with altered effects of acute ethanol on synaptic function in the IL-6 tg mice, EEG recordings showed a higher level of CNS activity in the IL-6 tg mice than in the non-tg mice during the period of withdrawal from an acute high dose of ethanol. These results suggest a potential role for neuroadaptive effects of ethanol-induced astrocyte production of IL-6 as a mediator or modulator of the actions of ethanol on the CNS, including persistent changes in CNS function that contribute to cognitive dysfunction and the development of alcohol dependence.

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IL-6 regulation of synaptic function in the CNS

Cited by 199 publications

References 176 publications

Intravitreous Injection of Interleukin-6 Leads to a Sprouting in the Retinotectal Pathway at Different Stages of Development

Intravitreous Injection of Interleukin-6 Leads to a Sprouting in the Retinotectal Pathway at Different Stages of Development

Allostatic Self-efficacy: A Metacognitive Theory of Dyshomeostasis-Induced Fatigue and Depression

Transgenic mice with increased astrocyte expression of IL-6 show altered effects of acute ethanol on synaptic function

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