Hypothalamus is a brain region that controls food intake and energy expenditure while sensing signals that convey information about energy status. Within the hypothalamus, molecularly and ...functionally distinct neurons work in concert under physiological conditions. However, under pathological conditions such as in diet-induced obesity (DIO) model, these neurons show dysfunctional firing patterns and distorted regulation by neurotransmitters and neurohormones. Concurrently, resident glial cells including astrocytes dramatically transform into reactive states. In particular, it has been reported that reactive astrogliosis is observed in the hypothalamus, along with various neuroinflammatory signals. However, how the reactive astrocytes control and modulate DIO by influencing neighboring neurons is not well understood. Recently, new lines of evidence have emerged indicating that these reactive astrocytes directly contribute to the pathology of obesity by synthesizing and tonically releasing the major inhibitory transmitter GABA. The released GABA strongly inhibits the neighboring neurons that control energy expenditure. These surprising findings shed light on the interplay between reactive astrocytes and neighboring neurons in the hypothalamus. This review summarizes recent discoveries related to the functions of hypothalamic reactive astrocytes in obesity and raises new potential therapeutic targets against obesity.
Recent studies have shown that not only neurons but astrocytes contain a considerable amount of γ-aminobutyric acid (GABA), which can be released and activate the receptors responsive to GABA. The ...purpose of this study is to test whether gliotransmitters from astrocytes may play a role in etiology of anxiety symptoms. Intracerebroventricular (i.c.v.) infusion of interleukin-1β (IL-1β), one of potent inflammatory cytokines, induced anxiety-like behaviors and activated the glial fibrillary acidic protein (GFAP) in the paraventricular nucleus (PVN) of the hypothalamus. Pretreatment with astrocytes toxin, l-α-aminoadipate (L-AAA) reduced anxiety-like behaviors and the GFAP expression in the PVN. Intraparaventricular nucleus (iPVN) infusion of IL-1β produced markedly anxiety-like behaviors and increased release of GABA from astrocytes. However, treatment of glial cell inhibitor, L-AAA or blocker of Bestrophin-1 (Best1), 5-Nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) markedly inactivated astrocytes and also reduced the anxiety-like behaviors. Treatment of L-AAA or NPPB decreased IL-1β-induced gliotransmitter GABA release measured by in vivo microdialysis. These results suggest that selective inhibition of astrocytes or astocytic GABA release in the PVN may serve as an effective therapeutic strategy for treating anxiety and affective disorders.
•IL-1β induces anxiety-like behaviors.•Astrocyte produces and releases GABA in IL-1β induced anxiety-like animal model.•L-AAA or NPPB administration normalized metabolism of neurotransmitter and astrocyte activation.•L-AAA or NPPB may serve an effective therapeutic strategy for treating anxietyresponses.
Sensory discrimination is essential for survival. However, how sensory information is finely controlled in the brain is not well defined. Here, we show that astrocytes control tactile acuity via ...tonic inhibition in the thalamus. Mechanistically, diamine oxidase (DAO) and the subsequent aldehyde dehydrogenase 1a1 (Aldh1a1) convert putrescine into GABA, which is released via Best1. The GABA from astrocytes inhibits synaptically evoked firing at the lemniscal synapses to fine-tune the dynamic range of the stimulation-response relationship, the precision of spike timing, and tactile discrimination. Our findings reveal a novel role of astrocytes in the control of sensory acuity through tonic GABA release.
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•Thalamic astrocytes synthesize GABA via DAO and Aldh1a1 to mediate tonic inhibition•Tonic GABA improves linearity and temporal fidelity of synaptically evoked TC firing•Astrocytic tonic GABA improves tactile discrimination performance
Kwak et al. report that astrocytes synthesize GABA using DAO and Aldh1a1 and release GABA through the Best1 channel to mediate tonic GABA in the thalamus. Astrocytic tonic GABA fine-tunes the dynamic range and precision of stimulation to response of TC firing, thus enhancing the performance of sensory discrimination of mice.
Monoamine oxidase-B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer's disease (AD) because of its association with aberrant γ-aminobutyric acid (GABA) production in ...reactive astrocytes. Although short-term treatment with irreversible MAO-B inhibitors, such as selegiline, improves cognitive deficits in AD patients, long-term treatments have shown disappointing results. We show that prolonged treatment with selegiline fails to reduce aberrant astrocytic GABA levels and rescue memory impairment in APP/PS1 mice, an animal model of AD, because of increased activity in compensatory genes for a GABA-synthesizing enzyme, diamine oxidase (DAO). We have developed a potent, highly selective, and reversible MAO-B inhibitor, KDS2010 (IC
= 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.
Monoamine oxidase (MAO) is believed to mediate the degradation of monoamine neurotransmitters, including dopamine, in the brain. Between the two types of MAO, MAO-B has been believed to be involved ...in dopamine degradation, which supports the idea that the therapeutic efficacy of MAO-B inhibitors in Parkinson's disease can be attributed to an increase in extracellular dopamine concentration. However, this belief has been controversial. Here, by utilizing in vivo phasic and basal electrochemical monitoring of extracellular dopamine with fast-scan cyclic voltammetry and multiple-cyclic square wave voltammetry and ex vivo fluorescence imaging of dopamine with GRAB
, we demonstrate that MAO-A, but not MAO-B, mainly contributes to striatal dopamine degradation. In contrast, our whole-cell patch-clamp results demonstrated that MAO-B, but not MAO-A, was responsible for astrocytic GABA-mediated tonic inhibitory currents in the rat striatum. We conclude that, in contrast to the traditional belief, MAO-A and MAO-B have profoundly different roles: MAO-A regulates dopamine levels, whereas MAO-B controls tonic GABA levels.
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.
Glucose hypometabolism in cortical structures after functional disconnection is frequently reported in patients with white matter diseases such as subcortical stroke. However, the molecular and ...cellular mechanisms have been poorly elucidated. Here we show, in an animal model of internal capsular infarct, that GABA-synthesizing reactive astrocytes in distant cortical areas cause glucose hypometabolism via tonic inhibition of neighboring neurons. We find that reversal of aberrant astrocytic GABA synthesis, by pharmacological inhibition and astrocyte-specific gene silencing of MAO-B, reverses the reduction in cortical glucose metabolism. Moreover, induction of aberrant astrocytic GABA synthesis by cortical injection of putrescine or adenovirus recapitulates cortical hypometabolism. Furthermore, MAO-B inhibition causes a remarkable recovery from post-stroke motor deficits when combined with a rehabilitation regimen. Collectively, our data indicate that cortical glucose hypometabolism in subcortical stroke is caused by aberrant astrocytic GABA and MAO-B inhibition and that attenuating cortical hypometabolism can be a therapeutic approach in subcortical stroke.
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•Capsular infarct induces neuronal atrophy and reactive astrogliosis in motor cortex•Tonic GABA from reactive astrocytes suppresses neuronal glucose metabolism•Inhibition of MAO-B, the GABA-synthesizing enzyme, restores glucose metabolism•Combined therapy of MAO-B inhibitor and rehabilitation causes functional recovery
Nam et al. demonstrate that excessive GABA from reactive astrocytes accounts for cortical glucose hypometabolism followed by subcortical stroke and impedes rehabilitation-aided motor functional recovery by aberrantly suppressing motor cortical neuronal activity. Thus, MAO-B, the astrocytic GABA-synthesizing enzyme, can be a therapeutic target for functional recovery after subcortical stroke.
Monoamine oxidase-B (MAOB) has been believed to mediate the degradation of monoamine neurotransmitters such as dopamine. However, this traditional belief has been challenged by demonstrating that it ...is not MAOB but MAOA which mediates dopamine degradation. Instead, MAOB mediates the aberrant synthesis of GABA and hydrogen peroxide (H
O
) in reactive astrocytes of Parkinson's disease (PD). Astrocytic GABA tonically suppresses the dopaminergic neuronal activity, whereas H
O
aggravates astrocytic reactivity and dopaminergic neuronal death. Recently discovered reversible MAOB inhibitors reduce reactive astrogliosis and restore dopaminergic neuronal activity to alleviate PD symptoms in rodents. In this perspective, we redefine the role of MAOB for the aberrant suppression and deterioration of dopaminergic neurons through excessive GABA and H
O
synthesis of reactive astrocytes in PD.
Reactive oxygen species (ROS) modulator 1 (Romo1) is a nuclear-encoded mitochondrial inner membrane protein known to regulate mitochondrial ROS production and to act as an essential redox sensor in ...mitochondrial dynamics. Although its physiological roles have been studied for a decade, the biophysical mechanisms that explain these activities of Romo1 are unclear. In this study, we report that Romo1 is a unique mitochondrial ion channel that differs from currently identified eukaryotic ion channels. Romo1 is a highly conserved protein with structural features of class II viroporins, which are virus-encoded nonselective cation channels. Indeed, Romo1 forms a nonselective cation channel with its amphipathic helical transmembrane domain necessary for pore-forming activity. Notably, channel activity was specifically inhibited by Fe
ions, an essential transition metal ion in ROS metabolism. Using structural bioinformatics, we designed an experimental data-guided structural model of Romo1 with a rational hexameric structure. We propose that Romo1 establishes a new category of viroporin-like nonselective cation channel in eukaryotes.
Delay discounting reflects the systematic reduction in the value of a consequence by delay to delivery. Theoretical and empirical work suggests that delay discounting is a key behavioral mechanism ...underlying substance use disorder. Existing work on cannabis use, however, is mixed with many studies reporting null results. The purpose of this review was to provide an in-depth assessment of the association between delay discounting and cannabis use. We conducted metaregression analyses to determine the omnibus correlation between delay discounting and cannabis use, and to evaluate task-based and sample-based moderators. Studies included evaluated an association between delay discounting and cannabis quantity-frequency or severity measures in human participants (27 studies, 61 effect sizes, 24,782 participants). A robust variance estimation method was used to account for dependence among effect sizes. A significant, but small, omnibus effect was observed (r = .082) in which greater cannabis use frequency or severity was associated with greater discounting. Incentive structure and outcome type were each significant moderators in a multiple moderator model such that incentivized tasks correlated with severity measures showed stronger associations (r = .234) than hypothetical tasks correlated with quantity-frequency measures (r = .029). Comparisons to historic effect size data supported the hypothesis that, at present, the relationship between cannabis use and delay discounting appears empirically smaller than for other substances. Future work should explore theoretical rationales explaining this modest relationship involving cannabis use and delay discounting, such as reflecting the smaller magnitude of perceived long-term clinical outcomes associated with cannabis compared to other substances.
Public Health Significance
How much individuals devalue future consequences (i.e., delay discounting) has been extensively studied for its relevance to substance use disorder. Fewer studies have evaluated associations with cannabis use and those that exist present mixed evidence. This meta-analysis summarizes this literature and finds that the association between delay discounting and cannabis use is, on average, small and is greater when evaluating severity of cannabis use with discounting assessed by incentivized tasks as compared to when evaluating use rates with discounting assessed by hypothetical tasks.
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