Low-intensity, low-frequency ultrasound (LILFU) is the next-generation, non-invasive brain stimulation technology for treating various neurological and psychiatric disorders. However, the underlying ...cellular and molecular mechanism of LILFU-induced neuromodulation has remained unknown. Here, we report that LILFU-induced neuromodulation is initiated by opening of TRPA1 channels in astrocytes. The Ca2+ entry through TRPA1 causes a release of gliotransmitters including glutamate through Best1 channels in astrocytes. The released glutamate activates NMDA receptors in neighboring neurons to elicit action potential firing. Our results reveal an unprecedented mechanism of LILFU-induced neuromodulation, involving TRPA1 as a unique sensor for LILFU and glutamate-releasing Best1 as a mediator of glia-neuron interaction. These discoveries should prove to be useful for optimization of human brain stimulation and ultrasonogenetic manipulations of TRPA1.
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•Ultrasound-induced neuromodulation is initiated by opening of TRPA1 in astrocytes•The Ca2+ entry through TRPA1 causes a release of glutamate through Best1 channels•The released glutamate activates NMDA receptors in neighboring neurons
Oh et al. show that TRPA1 is the molecular sensor and transducer for low-intensity, low-frequency ultrasound (LILFU). With TRPA1’s unique co-localization and cooperation with the glutamate-releasing Ca2+-activated Best1 at the microdomains of astrocytes, LILFU is capable of eliciting neuromodulation as a consequence of neuronal NMDAR activation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Key points
Neuronal activity causes astrocytic volume change via K+ uptake through TREK‐1 containing two‐pore domain potassium channels.
The volume transient is terminated by Cl− efflux through the ...Ca2+‐activated anion channel BEST1.
The source of the Ca2+ required to open BEST1 appears to be the stretch‐activated TRPA1 channel.
Intense neuronal activity is synaptically coupled with a physical change in astrocytes via volume transients.
The brain volume changes dynamically and transiently upon intense neuronal activity through a tight regulation of ion concentrations and water movement across the plasma membrane of astrocytes. We have recently demonstrated that an intense neuronal activity and subsequent astrocytic AQP4‐dependent volume transient are critical for synaptic plasticity and memory. We have also pharmacologically demonstrated a functional coupling between synaptic activity and the astrocytic volume transient. However, the precise molecular mechanisms of how intense neuronal activity and the astrocytic volume transient are coupled remain unclear. Here we utilized an intrinsic optical signal imaging technique combined with fluorescence imaging using ion sensitive dyes and molecular probes and electrophysiology to investigate the detailed molecular mechanisms in genetically modified mice. We report that a brief synaptic activity induced by a train stimulation (20 Hz, 1 s) causes a prolonged astrocytic volume transient (80 s) via K+ uptake through TREK‐1 containing two‐pore domain potassium (K2P) channels, but not Kir4.1 or NKCC1. This volume change is terminated by Cl− efflux through the Ca2+‐activated anion channel BEST1, but not the volume‐regulated anion channel TTYH. The source of the Ca2+ required to open BEST1 appears to be the stretch‐activated TRPA1 channel in astrocytes, but not IP3R2. In summary, our study identifies several important astrocytic ion channels (AQP4, TREK‐1, BEST1, TRPA1) as the key molecules leading to the neuronal activity‐dependent volume transient in astrocytes. Our findings reveal new molecular and cellular mechanisms for the synaptic coupling of intense neuronal activity with a physical change in astrocytes via volume transients.
Key points
Neuronal activity causes astrocytic volume change via K+ uptake through TREK‐1 containing two‐pore domain potassium channels.
The volume transient is terminated by Cl− efflux through the Ca2+‐activated anion channel BEST1.
The source of the Ca2+ required to open BEST1 appears to be the stretch‐activated TRPA1 channel.
Intense neuronal activity is synaptically coupled with a physical change in astrocytes via volume transients.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The underlying mechanisms of how positive emotional valence (e.g., pleasure) causes preference of an associated context is poorly understood. Here, we show that activation of astrocytic μ-opioid ...receptor (MOR) drives conditioned place preference (CPP) by means of specific modulation of astrocytic MOR, an exemplar endogenous Gi protein-coupled receptor (Gi-GPCR), in the CA1 hippocampus. Long-term potentiation (LTP) induced by a subthreshold stimulation with the activation of astrocytic MOR at the Schaffer collateral pathway accounts for the memory acquisition to induce CPP. This astrocytic MOR-mediated LTP induction is dependent on astrocytic glutamate released upon activation of the astrocytic MOR and the consequent activation of the presynaptic mGluR1. The astrocytic MOR-dependent LTP and CPP were recapitulated by a chemogenetic activation of astrocyte-specifically expressed Gi-DREADD hM4Di. Our study reveals that the transduction of inhibitory Gi-signaling into augmented excitatory synaptic transmission through astrocytic glutamate is critical for the acquisition of contextual memory for CPP.
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•Hippocampal astrocytic μ-opioid receptor (MOR) activation drives conditioned place preference (CPP)•Astrocytic MOR activation enhances synaptic plasticity at the Schaffer collateral pathway•Chemogenetic activation of astrocytic Gi-DREADD recapitulates MOR-mediated LTP and CPP
Nam et al. demonstrate that activation of hippocampal astrocytic μ-opioid receptor causes glutamate release, which increases the release probability by neuronal presynaptic mGluR1 activation and potentiates synaptic plasticity at the SC-CA1 pathway. This enhanced synaptic transmission and synaptic plasticity account for the acquisition of memory associated with CPP.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Clinically relevant, in Parkinson's disease patients, despite a marked reduction in TH expression in SNpc neurons, a substantial number of these neurons remain viable in the mild stages, contrasting ...with their extensive death in the severe stages.7 In stroke, diaschisis, characterized by glucose hypometabolism in regions distant from the injury site, is exacerbated by elevated GABA tone via reactive astrocytes.8 This elevated GABA tone inhibits synaptic activity in adjacent cortical neurons, hindering functional recovery, particularly in motor deficits.8 In depression, increased tonic inhibition due to MAO-B-dependent GABA synthesis has been reported in the hippocampus of social deprivation mice13 and the medial prefrontal cortex of Flinders Sensitive Line rat models9 of depression, leading to suppressed long-term potentiation. ...reversible MAO-B inhibitors such as safinamide (Xadago) and the newly developed KDS2010 (Tisolagiline) have less compensatory effects because they compete with the substrate and consequently leave MAO-B intact.5 This contrast strongly suggests the use of reversible, but not irreversible, MAO-B inhibitors as a long-term treatment to reduce MAO-B-dependent GABA synthesis in pathological conditions. ...the elevated GABA tone resulting from increased MAO-B activity in reactive astrocytes can serve as a potential diagnostic marker for brain diseases. ...the regulation of GABA tone, especially through astrocytes, plays a crucial role in our understanding of both brain function and dysfunction.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Impaired ion channels regulating Golgi pH lead to structural alterations in the Golgi apparatus, such as fragmentation, which is found, along with cognitive impairment, in Alzheimer’s ...disease. However, the causal relationship between altered Golgi structure and cognitive impairment remains elusive due to the lack of understanding of ion channels in the Golgi apparatus of brain cells. Here, we identify that a transmembrane protein TMEM87A, renamed Golgi-pH-regulating cation channel (GolpHCat), expressed in astrocytes and neurons that contributes to hippocampus-dependent memory. We find that GolpHCat displays unique voltage-dependent currents, which is potently inhibited by gluconate. Additionally, we gain structural insights into the ion conduction through GolpHCat at the molecular level by determining three high-resolution cryogenic-electron microscopy structures of human GolpHCat. GolpHCat-knockout mice show fragmented Golgi morphology and altered protein glycosylation and functions in the hippocampus, leading to impaired spatial memory. These findings suggest a molecular target for Golgi-related diseases and cognitive impairment.
Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a ...neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions.
Nicotinamide adenine dinucleotide (NAD)
serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide ...phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD
salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD
salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT-NAD
-CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca
signals and compromised Ca
responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD
salvage pathway, along with its downstream CD38, to HFD-induced obesity.
Astroglial cells were long considered as structural and metabolic supporting cells are which do not directly participate in information processing in the brain. Discoveries of responsiveness of ...astrocytes to synaptically-released glutamate and their capability to release agonists of glutamate receptors awakened extensive studies of glia-neuron communications and led to the revolutionary changes in our understanding of brain cellular networks. Nowadays, astrocytes are widely acknowledged as inseparable element of glutamatergic synapses and role for glutamatergic astrocyte-neuron interactions in the brain computation is emerging.
Astroglial glutamate receptors, in particular of NMDA, mGluR3 and mGluR5 types, can activate a variety of molecular cascades leading astroglial-driven modulation of extracellular levels of glutamate and activity of neuronal glutamate receptors. Their preferential location to the astroglial perisynaptic processes facilitates interaction of astrocytes with individual excitatory synapses. Bi-directional glutamatergic communication between astrocytes and neurons underpins a complex, spatially-distributed modulation of synaptic signalling thus contributing to the enrichment of information processing by the neuronal networks.
Still, further research is needed to bridge the substantial gaps in our understanding of mechanisms and physiological relevance of astrocyte-neuron glutamatergic interactions, in particular ability of astrocytes directly activate neuronal glutamate receptors by releasing glutamate and, arguably, d-Serine. An emerging roles for aberrant changes in glutamatergic astroglial signalling, both neuroprotective and pathogenic, in neurological and neurodegenerative diseases also require further investigation.
This article is part of the Neuropharmacology Special Issue on ‘Glutamate Receptors - The Glutamatergic Synapse’.
•Glutamate receptors underlie ability of astrocytes to detect neuronal activity.•Astroglial uptake and release of glutamate affect synaptic transmission and plasticity.•Astrocytic mGluR and NMDA receptors modulate activity of glutamate transporters.•Expression of glutamate receptors in astrocytes changes in pathological context.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, SAZU, SBCE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The neuronal activity-dependent change in the manner in which light is absorbed or scattered in brain tissue is called the intrinsic optical signal (IOS), and provides label-free, minimally invasive, ...and high spatial (~100 µm) resolution imaging for visualizing neuronal activity patterns. IOS imaging in isolated brain slices measured at an infrared wavelength (>700 nm) has recently been attributed to the changes in light scattering and transmittance due to aquaporin-4 (AQP4)-dependent astrocytic swelling. The complexity of functional interactions between neurons and astrocytes, however, has prevented the elucidation of the series of molecular mechanisms leading to the generation of IOS. Here, we pharmacologically dissected the IOS in the acutely prepared brain slices of the stratum radiatum of the hippocampus, induced by 1 s/20 Hz electrical stimulation of Schaffer-collateral pathway with simultaneous measurement of the activity of the neuronal population by field potential recordings. We found that 55% of IOSs peak upon stimulation and originate from postsynaptic AMPA and NMDA receptors. The remaining originated from presynaptic action potentials and vesicle fusion. Mechanistically, the elevated extracellular glutamate and K
during synaptic transmission were taken up by astrocytes via a glutamate transporter and quinine-sensitive K2P channel, followed by an influx of water via AQP-4. We also found that the decay of IOS is mediated by the DCPIB- and NPPB-sensitive anion channels in astrocytes. Altogether, our results demonstrate that the functional coupling between synaptic activity and astrocytic transient volume change during excitatory synaptic transmission is the major source of IOS.
Synaptically localized NMDA receptors (NMDARs) play a crucial role in important cognitive functions by mediating synaptic transmission and plasticity. In contrast, a tonic NMDAR current, thought to ...be mediated by extrasynaptic NMDARs, has a less clear function. This review provides a comprehensive overview of tonic NMDAR currents, focusing on their roles in synaptic transmission/plasticity and their impact on cognitive functions and psychiatric disorders. We discuss the roles of 3 endogenous ligands (i.e., glutamate, glycine, and D-serine) and receptors in mediating tonic NMDAR currents and explore the diverse mechanisms that regulate tonic NMDAR currents. In light of recent controversies surrounding the source of D-serine, we highlight the recent findings suggesting that astrocytes release D-serine to modulate tonic NMDAR currents and control cognitive flexibility. Furthermore, we propose distinct roles of neuronal and astrocytic D-serine in different locations and their implications for synaptic regulation and cognitive functions. The potential roles of tonic NMDAR currents in various psychiatric disorders, such as schizophrenia and autism spectrum disorder, are discussed in the context of the NMDAR hypofunction hypothesis. By presenting the mechanisms by which various cells, particularly astrocytes, regulate tonic NMDAR currents, we aim to stimulate future research in NMDAR hypofunction- or hyperfunction-related psychiatric disorders. This review not only provides a better understanding of the complex interplay between tonic NMDAR currents and cognitive functions but also sheds light on its potential therapeutic target for the treatment of various psychiatric disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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