During nervous system development, neurons extend axons along well-defined pathways. The current understanding of axon pathfinding is based mainly on chemical signaling. However, growing neurons ...interact not only chemically but also mechanically with their environment. Here we identify mechanical signals as important regulators of axon pathfinding. In vitro, substrate stiffness determined growth patterns of Xenopus retinal ganglion cell axons. In vivo atomic force microscopy revealed a noticeable pattern of stiffness gradients in the embryonic brain. Retinal ganglion cell axons grew toward softer tissue, which was reproduced in vitro in the absence of chemical gradients. To test the importance of mechanical signals for axon growth in vivo, we altered brain stiffness, blocked mechanotransduction pharmacologically and knocked down the mechanosensitive ion channel piezo1. All treatments resulted in aberrant axonal growth and pathfinding errors, suggesting that local tissue stiffness, read out by mechanosensitive ion channels, is critically involved in instructing neuronal growth in vivo.
Just as the epigenome, the proteome and the electrophysiological properties of a cell influence its function, so too do its intrinsic mechanical properties and its extrinsic mechanical environment. ...This is especially true for neurons of the central nervous system (CNS) as long‐term maintenance of synaptic connections relies on efficient axonal transport machinery and structural stability of the cytoskeleton. Recent reports suggest that profound physical changes occur in the CNS microenvironment with advancing age which, in turn, will impact highly mechanoresponsive neurons and glial cells. Here, we discuss the complex and inhomogeneous mechanical structure of CNS tissue, as revealed by recent mechanical measurements on the brain and spinal cord, using techniques such as magnetic resonance elastography and atomic force microscopy. Moreover, ageing, traumatic brain injury, demyelination and neurodegeneration can perturb the mechanical properties of brain tissue and trigger mechanobiological signalling pathways in neurons, glia and cerebral vasculature. It is, therefore, very likely that significant changes in cell and tissue mechanics contribute to age‐related cognitive decline and deficits in memory formation which are accelerated and magnified in neurodegenerative states, such as Alzheimer's disease. Importantly, we are now beginning to understand how neuronal and glial cell mechanics and brain tissue mechanobiology are intimately linked with neurophysiology and cognition.
The mechanical properties of brain tissue can influence cell migration, neurogenesis, neurite outgrowth, regeneration and neuronal excitability. The extracellular microenvironment of neurons and glia changes in neurodegenerative disease states and, to a lesser extent, with “healthy ageing.” Understanding how perturbed mechanotransduction signalling influences the biochemistry and physiology of neurons and glia may reveal new drug targets for neurodegenerative disorders.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Injury to the central nervous system (CNS) alters the molecular and cellular composition of neural tissue and leads to glial scarring, which inhibits the regrowth of damaged axons. Mammalian glial ...scars supposedly form a chemical and mechanical barrier to neuronal regeneration. While tremendous effort has been devoted to identifying molecular characteristics of the scar, very little is known about its mechanical properties. Here we characterize spatiotemporal changes of the elastic stiffness of the injured rat neocortex and spinal cord at 1.5 and three weeks post-injury using atomic force microscopy. In contrast to scars in other mammalian tissues, CNS tissue significantly softens after injury. Expression levels of glial intermediate filaments (GFAP, vimentin) and extracellular matrix components (laminin, collagen IV) correlate with tissue softening. As tissue stiffness is a regulator of neuronal growth, our results may help to understand why mammalian neurons do not regenerate after injury.
An essential aspect of normal brain function is the bidirectional interaction and communication between neurons and neighbouring glial cells. To this end, the brain has evolved ligand–receptor ...partnerships that facilitate crosstalk between different cell types. The chemokine, fractalkine (FKN), is expressed on neuronal cells, and its receptor, CX3CR1, is predominantly expressed on microglia. This review focuses on several important functional roles for FKN/CX3CR1 in both health and disease of the central nervous system. It has been posited that FKN is involved in microglial infiltration of the brain during development. Microglia, in turn, are implicated in the developmental synaptic pruning that occurs during brain maturation. The abundance of FKN on mature hippocampal neurons suggests a homeostatic non-inflammatory role in mechanisms of learning and memory. There is substantial evidence describing a role for FKN in hippocampal synaptic plasticity. FKN, on the one hand, appears to prevent excess microglial activation in the absence of injury while promoting activation of microglia and astrocytes during inflammatory episodes. Thus, FKN appears to be neuroprotective in some settings, whereas it contributes to neuronal damage in others. Many progressive neuroinflammatory disorders that are associated with increased microglial activation, such as Alzheimer's disease, show disruption of the FKN/CX3CR1 communication system. Thus, targeting CX3CR1 receptor hyperactivation with specific antagonists in such neuroinflammatory conditions may eventually lead to novel neurotherapeutics.
Neuropathic pain can arise from lesions to peripheral or central nerve fibres leading to spontaneous action potential generation and a lowering of the nociceptive threshold. Clinically, neuropathic ...pain can manifest in many chronic disease states such as cancer, diabetes or multiple sclerosis (MS). The bioactive lipid, lysophosphatidic acid (LPA), via activation of its receptors (LPARs), is thought to play a central role in both triggering and maintaining neuropathic pain. In particular, following an acute nerve injury, the excitatory neurotransmitters glutamate and substance P are released from primary afferent neurons leading to upregulated synthesis of lysophosphatidylcholine (LPC), the precursor for LPA production. LPC is converted to LPA by autotaxin (ATX), which can then activate macrophages/microglia and modulate neuronal functioning. A ubiquitous feature of animal models of neuropathic pain is demyelination of damaged nerves. It is thought that LPA contributes to demyelination through several different mechanisms. Firstly, high levels of LPA are produced following macrophage/microglial activation that triggers a self-sustaining feed-forward loop of de novo LPA synthesis. Secondly, macrophage/microglial activation contributes to inflammation-mediated demyelination of axons, thus initiating neuropathic pain. Therefore, targeting LPA production and/or the family of LPA-activated G protein-coupled receptors (GPCRs) may prove to be fruitful clinical approaches to treating demyelination and the accompanying neuropathic pain. This review discusses our current understanding of the role of LPA/LPAR signalling in the initiation of neuropathic pain and suggests potential targeted strategies for its treatment.
This article is part of the Special Issue entitled ‘Lipid Sensing G Protein-Coupled Receptors in the CNS’.
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•Neuropathic pain (NP) is a multifactorial pathological state with no cure.•Increased LPA synthesis after nerve injury can trigger demyelination, causing NP.•LPA/LPAR signalling contributes to maintenance of NP.•New therapeutics targeting LPA production and signalling may be effective in alleviating NP.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
Sphingosine 1‐phosphate receptors (S1PR) are G protein‐coupled and compose a family with five subtypes, S1P1R–S1P5R. The drug Gilenya® (Novartis, Basel, Switzerland) (Fingolimod; FTY720) targets ...S1PRs and was the first oral therapy for patients with relapsing‐remitting multiple sclerosis (MS). The phosphorylated form of FTY720 (pFTY720) binds S1PRs causing initial agonism, then subsequent receptor internalization and functional antagonism. Internalization of S1P1R attenuates sphingosine 1‐phosphate (S1P)‐mediated egress of lymphocytes from lymph nodes, limiting aberrant immune function in MS. pFTY720 also exerts direct actions on neurons and glial cells which express S1PRs. In this study, we investigated the regulation of pro‐inflammatory chemokine release by S1PRs in enriched astrocytes and microglial cultures. Astrocytes and microglia were stimulated with lipopolysaccharide (LPS) and increases in C‐X‐C motif chemokine 5 (CXCL5), also known as LIX (lipopolysaccharide‐induced CXC chemokine) expression were quantified. Results showed that pFTY720 attenuated LPS‐induced CXCL5 (LIX) protein release from astrocytes, as did the S1P1R selective agonist, SEW2871. In addition, pFTY720 blocked messenger ribonucleic acid (mRNA) transcription of the chemokines, (i) CXCL5/LIX, (ii) C‐X‐C motif chemokine 10 (CXCL10) also known as interferon gamma‐induced protein 10 (IP10) and (iii) chemokine (C‐C motif) ligand 2 (CCL2) also known as monocyte chemoattractant protein 1 (MCP1). Interestingly, inhibition of sphingosine kinase attenuated LPS‐induced increases in mRNA levels of all three chemokines, suggesting that LPS‐TLR4 (Toll‐like receptor 4) signalling may enhance chemokine expression via S1P‐S1PR transactivation. Lastly, these observations were not limited to astrocytes since we also found that pFTY720 attenuated LPS‐induced release of CXCL5 from microglia. These data highlight a role for S1PR signalling in regulating the levels of chemokines in glial cells and support the notion that pFTY720 efficacy in multiple sclerosis may involve the direct modulation of astrocytes and microglia.
In addition to its immunomodulatory actions, the multiple sclerosis (MS) drug FTY720 binds to membrane sphingosine 1‐phosphate (S1P) receptors and regulates the release of inflammatory mediators from glial cells in the central nervous system. In this study, we found that lipopolysaccharide (LPS) induced the release of chemokines, in particular C‐X‐C motif chemokine 5 (CXCL5), from astrocytes and microglia and that phosphorylated FTY720 (pFTY720) blocks this process. Our data suggest that LPS induces transactivation of glial S1P receptors, in a sphingosine kinase‐dependent manner, resulting in chemokine synthesis and that pFTY720 interrupts this signalling cascade by causing intracellular accumulation of membrane S1P1R. Therefore, FTY720's therapeutic effects in MS may include modulation of neuroinflammation through direct regulation of S1PR signalling in astrocytes and microglia.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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•Cellular and psychological stress elevate nuclear REST in stress-responsive neurons.•REST epigenetically determines target gene expression following stress.•REST protects neurons ...from oxidative stress and hyperexcitability.•REST inhibits premature neural stem cell depletion and amyloid-β1-42 pathology.•Modulation of REST activity is a promising strategy to promote stress resilience.
The transcriptional repressor REST (Repressor Element-1 Silencing Transcription factor) is a key modulator of the neuronal epigenome and targets genes involved in neuronal differentiation, axonal growth, vesicular transport, ion channel conductance and synaptic plasticity. Whilst its gene expression-modifying properties have been examined extensively in neuronal development, REST’s response towards stress-induced neuronal insults has only recently been explored. Overall, REST appears to be an ideal candidate to fine-tune neuronal gene expression following different forms of cellular, neuropathological, psychological and physical stressors. Upregulation of REST is reportedly protective against premature neural stem cell depletion, neuronal hyperexcitability, oxidative stress, neuroendocrine system dysfunction and neuropathology. In contrast, neuronal REST activation has also been linked to neuronal dysfunction and neurodegeneration. Here, we highlight key findings and discrepancies surrounding our current understanding of REST’s function in neuronal adaptation to stress and explore its potential role in neuronal stress resilience in the young and ageing brain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Neurons and glial cells of the central nervous system (CNS) release extracellular vesicles (EVs) to the interstitial fluid of the brain and spinal cord parenchyma. EVs contain proteins, nucleic acids ...and lipids that can be taken up by, and modulate the behaviour of, neighbouring recipient cells. The functions of EVs have been extensively studied in the context of neurodegenerative diseases. However, mechanisms involved in EV‐mediated neuron–glial communication under physiological conditions or healthy ageing remain unclear. A better understanding of the myriad roles of EVs in CNS homeostasis is essential for the development of novel therapeutics to alleviate and reverse neurological disturbances of ageing. Proteomic studies are beginning to reveal cell type‐specific EV cargo signatures that may one day allow us to target specific neuronal or glial cell populations in the treatment of debilitating neurological disorders. This review aims to synthesise the current literature regarding EV‐mediated cell–cell communication in the brain, predominantly under physiological conditions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
People that develop extracranial cancers often display co‐morbid neurological disorders, such as anxiety, depression and cognitive impairment, even before commencement of chemotherapy. This suggests ...bidirectional crosstalk between non‐CNS tumours and the brain, which can regulate peripheral tumour growth. However, the reciprocal neurological effects of tumour progression on brain homeostasis are not well understood. Here, we review brain regions involved in regulating peripheral tumour development and how they, in turn, are adversely affected by advancing tumour burden. Tumour‐induced activation of the immune system, blood–brain barrier breakdown and chronic neuroinflammation can lead to circadian rhythm dysfunction, sleep disturbances, aberrant glucocorticoid production, decreased hippocampal neurogenesis and dysregulation of neural network activity, resulting in depression and memory impairments. Given that cancer‐related cognitive impairment diminishes patient quality of life, reduces adherence to chemotherapy and worsens cancer prognosis, it is essential that more research is focused at understanding how peripheral tumours affect brain homeostasis.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Astrocytes are important for information processing in the brain and they achieve this by fine‐tuning neuronal communication via continuous uptake and release of biochemical modulators of ...neurotransmission and synaptic plasticity. Often overlooked are their important functions in mechanosensation. Indeed, astrocytes can detect pathophysiological changes in the mechanical properties of injured, ageing, or degenerating brain tissue. We have recently shown that astrocytes surrounding mechanically‐stiff amyloid plaques upregulate the mechanosensitive ion channel, Piezo1. Moreover, ageing transgenic Alzheimer's rats harboring a chronic peripheral bacterial infection displayed enhanced Piezo1 expression in amyloid plaque‐reactive astrocytes of the hippocampus and cerebral cortex. Here, we have shown that the bacterial endotoxin, lipopolysaccharide (LPS), also upregulates Piezo1 in primary mouse cortical astrocyte cultures in vitro. Activation of Piezo1, via the small molecule agonist Yoda1, enhanced Ca2+ influx in both control and LPS‐stimulated astrocytes. Moreover, Yoda1 augmented intracellular Ca2+ oscillations but decreased subsequent Ca2+ influx in response to adenosine triphosphate (ATP) stimulation. Neither blocking nor activating Piezo1 affected cell viability. However, LPS‐stimulated astrocyte cultures exposed to the Piezo1 activator, Yoda1, migrated significantly slower than reactive astrocytes treated with the mechanosensitive channel‐blocking peptide, GsMTx4. Furthermore, our data show that activating Piezo1 channels inhibits the release of cytokines and chemokines, such as IL‐1β, TNFα, and fractalkine (CX3CL1), from LPS‐stimulated astrocyte cultures. Taken together, our results suggest that astrocytic Piezo1 upregulation may act to dampen neuroinflammation and could be a useful drug target for neuroinflammatory disorders of the brain.
Main Points
Activation of Piezo1 channels in LPS‐stimulated astrocytes induces calcium influx and augments intracellular calcium oscillations.
Piezo1 activation inhibits the release of pro‐inflammatory cytokines, IL‐1β and TNFα, from LPS‐stimulated astrocytes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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