A G protein‐coupled α7 nicotinic receptor regulates signaling and <scp>TNF</scp>‐α release in microglia

King, Justin R.; Gillevet, Trudy C.; Kabbani, Nadine

doi:10.1002/2211-5463.12270

Cited by 66 publications

(55 citation statements)

References 61 publications

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“…There are multiple cell types in the hippocampus that express functional α7 nAChRs, including interneurons, astrocytes, microglia as well as immature granule cells (John et al 2015; Jones and Yakel 1997; King et al 2017; Sharma and Vijayaraghavan 2001; Shen and Yakel 2012; Shytle et al 2004). We investigated if the loss of α7 nAChRs in nestin + NSCs prior to or during adult neurogenesis was responsible for the changes in adult neurogenesis we had seen in male (but not female) mice; that is whether these changes are a result of cell autonomous or simple feed-back regulation.…”

Section: Resultsmentioning

confidence: 99%

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

Otto

Yakel

2018

Brain Struct Funct

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Disruption in cholinergic signaling has been linked to many environmental and/or pathological conditions known to modify adult neurogenesis. The α7 nAChRs are in the family of cys-loop receptor channels which have been shown to be neuroprotective in adult neurons and are thought to be critical for survival and integration of immature neurons. However, in developing neurons, poor calcium buffering may cause α7 nAChR activation to be neurotoxic. To investigate whether the α7 nAChR regulates neurogenesis in the hippocampus, we used a combination of mouse genetics and imaging to quantify neural stem cell (NSC) densities located in the dentate gyrus of adult mice. In addition, we considered whether the loss of α7 nAChRs had functional consequences on a spatial discrimination task that is thought to rely on pattern separation mechanisms. We found that the loss of α7 nAChRs resulted in increased neurogenesis in male mice only, while female mice showed increased cell divisions and intermediate progenitors but no change in neurogenesis. Knocking out the α7 nAChR from nestin+ NSCs and their progeny showed signaling in these cells contributes to regulating neurogenesis. In addition, male, but not female, mice lacking α7 nAChRs performed significantly worse in the spatial discrimination task. This task was sexually dimorphic in wild-type mice, but not in the absence of α7 nAChRs. We conclude that α7 nAChRs regulate adult neurogenesis and impact spatial discrimination function in male, but not female mice, via a mechanism involving nestin+ NSCs and their progeny.

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Section: Resultsmentioning

confidence: 99%

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

Otto

Yakel

2018

Brain Struct Funct

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“…Nicotinic receptors, in particular α7 receptor (Y. Sun et al, ; King, Gillevet, & Kabbani, ), decreases p‐NF‐κB and its p65 subunit and inhibits p38 mitogen‐activated protein kinase (p38‐MAPK), a key player of inflammatory microglia response (Lawson, Dobrikova, Shveygert, & Gromeier, ) (Figure ), while upregulates antioxidant genes, promoting a pro‐regenerative microglial state (Z. Han et al, ). Sphingosine‐1‐phosphate (S1P) receptors downregulate pro‐inflammatory cytokines and enhance pro‐regenerative responses after intracerebral hemorrhage (Marfia et al, ; Noda, Takeuchi, Mizuno, & Suzumura, ).…”

Section: Receptor and Channels Promoting Anti‐inflammatory Microglia mentioning

confidence: 99%

“…Nicotinic receptors, in particular α7 receptor (Y. Sun et al, 2013;King, Gillevet, & Kabbani, 2017), decreases p-NF-κB and its p65 subunit and inhibits p38 mitogen-activated protein kinase (p38-MAPK), a key player of inflammatory microglia response (Lawson, Dobrikova, Shveygert, & Gromeier, 2013) (Figure 1), while upregulates antioxidant genes, promoting a pro-regenerative microglial state (Z. Han et al, 2014).…”

Section: Histamine and Other Neurotransmitter Receptorsmentioning

confidence: 99%

How to reprogram microglia toward beneficial functions

Fumagalli

Lombardi

Gressèns

et al. 2018

Glia

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Microglia, brain cells of nonneural origin, orchestrate the inflammatory response to diverse insults, including hypoxia/ischemia or maternal/fetal infection in the perinatal brain. Experimental studies have demonstrated the capacity of microglia to recognize pathogens or damaged cells activating a cytotoxic response that can exacerbate brain damage. However, microglia display an enormous plasticity in their responses to injury and may also promote resolution stages of inflammation and tissue regeneration. Despite the critical role of microglia in brain pathologies, the cellular mechanisms that govern the diverse phenotypes of microglia are just beginning to be defined. Here we review emerging strategies to drive microglia toward beneficial functions, selectively reporting the studies which provide insights into molecular mechanisms underlying the phenotypic switch. A variety of approaches have been proposed which rely on microglia treatment with pharmacological agents, cytokines, lipid messengers, or microRNAs, as well on nutritional approaches or therapies with immunomodulatory cells. Analysis of the molecular mechanisms relevant for microglia reprogramming toward pro-regenerative functions points to a central role of energy metabolism in shaping microglial functions. Manipulation of metabolic pathways may thus provide new therapeutic opportunities to prevent the deleterious effects of inflammatory microglia and to control excessive inflammation in brain disorders.

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“…In contrast, nicotine suppresses reactive microglia in the adult brain (Li et al, 2016;Noda & Kobayashi, 2017), and blocks LPS-induced increases in microglial activation and expression of Toll-like receptor 4 (TLR4, see below; Kim et al, 2014;Li et al, 2016). The anti-inflammatory state produced by nicotine results from activation of the a7 nicotinic acetylcholine receptor (nAChR) (Shytle et al, 2004;Noda & Kobayashi, 2017), possibly in a metabotropic signaling mode (King et al, 2017). Astrocytes have also been shown to express a7 nAChRs (Shen & Yakel, 2012), which modulate synaptic responsiveness by controlling glial release of the N-methyl D-aspartate (NMDA) receptor co-agonist, D-serine (Papouin et al, 2017).…”

Section: Drugs Of Abuse Promote Reactive Gliamentioning

confidence: 99%

Glial mechanisms underlying substance use disorders

Linker

Cross

Leslie

2018

Eur J of Neuroscience

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Addiction is a devastating disorder that produces persistent maladaptive changes to the central nervous system, including glial cells. Although there is an extensive body of literature examining the neuronal mechanisms of substance use disorders, effective therapies remain elusive. Glia, particularly microglia and astrocytes, have an emerging and meaningful role in a variety of processes beyond inflammation and immune surveillance, and may represent a promising therapeutic target. Indeed, glia actively modulate neurotransmission, synaptic connectivity and neural circuit function, and are critically poised to contribute to addictive‐like brain states and behaviors. In this review, we argue that glia influence the cellular, molecular, and synaptic changes that occur in neurons following drug exposure, and that this cellular relationship is critically modified following drug exposure. We discuss direct actions of abused drugs on glial function through immune receptors, such as Toll‐like receptor 4, as well as other mechanisms. We highlight how drugs of abuse affect glia‐neural communication, and the profound effects that glial‐derived factors have on neuronal excitability, structure, and function. Recent research demonstrates that glia have brain region‐specific functions, and glia in different brain regions have distinct contributions to drug‐associated behaviors. We will also evaluate the evidence demonstrating that glial activation is essential for drug reward and drug‐induced dopamine release, and highlight clinical evidence showing that glial mechanisms contribute to drug abuse liability. In this review, we synthesize the extensive evidence that glia have a unique, pivotal, and underappreciated role in the development and maintenance of addiction.

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A G protein‐coupled α7 nicotinic receptor regulates signaling and TNF‐α release in microglia

Cited by 66 publications

References 61 publications

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

How to reprogram microglia toward beneficial functions

Glial mechanisms underlying substance use disorders

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