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.
Tonic inhibition in the brain is mediated through an activation of extrasynaptic GABAA receptors by the tonically released GABA, resulting in a persistent GABAergic inhibitory action. It is one of ...the key regulators for neuronal excitability, exerting a powerful action on excitation/inhibition balance. We have previously reported that astrocytic GABA, synthesized by monoamine oxidase B (MAOB), mediates tonic inhibition via GABA-permeable bestrophin 1 (Best1) channel in the cerebellum. However, the role of astrocytic GABA in regulating neuronal excitability, synaptic transmission, and cerebellar brain function has remained elusive. Here, we report that a reduction of tonic GABA release by genetic removal or pharmacological inhibition of Best1 or MAOB caused an enhanced neuronal excitability in cerebellar granule cells (GCs), synaptic transmission at the parallel fiber-Purkinje cell (PF-PC) synapses, and motor performance on the rotarod test, whereas an augmentation of tonic GABA release by astrocyte-specific overexpression of MAOB resulted in a reduced neuronal excitability, synaptic transmission, and motor performance. The bidirectional modulation of astrocytic GABA by genetic alteration of Best1 or MAOB was confirmed by immunostaining and in vivo microdialysis. These findings indicate that astrocytes are the key player in motor coordination through tonic GABA release by modulating neuronal excitability and could be a good therapeutic target for various movement and psychiatric disorders, which show a disturbed excitation/inhibition balance.
Abstract
Neuronal firing patterns, which are crucial for determining the nature of encoded information, have been widely studied; however, the molecular identity and cellular mechanisms of ...spike-frequency adaptation are still not fully understood. Here we show that spike-frequency adaptation in thalamocortical (TC) neurons is mediated by the Ca
2+
-activated Cl
−
channel (CACC) anoctamin-2 (ANO2). Knockdown of ANO2 in TC neurons results in significantly reduced spike-frequency adaptation along with increased tonic spiking. Moreover, thalamus-specific knockdown of ANO2 increases visceral pain responses. These results indicate that ANO2 contributes to reductions in spike generation in highly activated TC neurons and thereby restricts persistent information transmission.
Light is a powerful external cue modulating the biological rhythm of internal clock neurons in the suprachiasmatic nucleus (SCN). GABA signaling in SCN is critically involved in this process. Both ...phasic and tonic modes of GABA signaling exist in SCN. Of the two modes, the tonic mode of GABA signaling has been implicated in light-mediated synchrony of SCN neurons. However, modulatory effects of external light on tonic GABA signalling are yet to be explored. Here, we systematically characterized electrophysiological properties of the clock neurons and determined the spatio-temporal profiles of tonic GABA current. Based on the whole-cell patch-clamp recordings from 76 SCN neurons, the cells with large tonic GABA current (>15 pA) were more frequently found in dorsal SCN. Moreover, tonic GABA current in SCN was highly correlated with the frequency of spontaneous inhibitory postsynaptic current (sIPSC), raising a possibility that tonic GABA current is due to spill-over from synaptic release. Interestingly, tonic GABA current was inversely correlated with slice-to-patch time interval, suggesting a critical role of retinal light exposure in intact brain for an induction of tonic GABA current in SCN. To test this possibility, we obtained meticulously prepared retina-attached SCN slices and successfully recorded tonic and phasic GABA signaling in SCN neurons. For the first time, we observed an early-onset, long-lasting tonic GABA current, followed by a slow-onset, short-lasting increase in the phasic GABA frequency, upon direct light-illumination of the attached retina. This result provides the first evidence that external light cue can directly trigger both tonic and phasic GABA signaling in SCN cell. In conclusion, we propose tonic GABA as the key mediator of external light in SCN.
A single stressful event can cause morphologic and functional changes in neurons and even malfunction of vascular systems, which can lead to acute stress disorder or post-traumatic stress disorder. ...However, there is a lack of evidence regarding how acute stress impacts neuronal activity, the concurrent vascular response, and the relationship between these two factors, which is defined as neurovascular coupling. Here, using
two-photon imaging, we found that NMDA-evoked calcium transients of excitatory neurons were impaired and that vasodilation of penetrating arterioles was concomitantly disrupted in acutely stressed male mice. Furthermore, acute stress altered the relationship between excitatory neuronal calcium coherence and vascular responses. By measuring NMDA-evoked excitatory and inhibitory neuronal calcium activity in acute brain slices, we confirmed that neuronal coherence both between excitatory neurons and between excitatory and inhibitory neurons was reduced by acute stress but restored by blockade of glucocorticoid receptor signaling. Furthermore, the ratio of sEPSCs to sIPSCs was altered by acute stress, suggesting that the excitation-inhibition balance was disrupted by acute stress. In summary,
,
, and whole-cell recording studies demonstrate that acute stress modifies excitatory-inhibitory neuronal coherence, disrupts the excitation-inhibition balance, and causes consequent neurovascular coupling changes, providing critical insights into the neural mechanism of stress-induced disorders.
Acute stress can cause pathologic conditions, such as acute stress disorder and post-traumatic stress disorder, by affecting the functions of neurons and blood vessels. However, investigations into the impacts of acute stress on neurovascular coupling, the tight connection between local neural activity and subsequent blood flow changes, are lacking. Through investigations at the
,
, and whole-cell recording levels, we found that acute stress alters the NMDA-evoked vascular response, impairs the function and coherence of excitatory and inhibitory neurons, and disrupts the excitatory and inhibitory balance. These novel findings provide insights into the relevance of the excitatory-inhibitory balance, neuronal coherence, and neurovascular coupling to stress-induced disorders.
Objectives:
Currently, epidemiological data on allergic rhinitis collected through the skin prick test are scarce. Moreover, the relationship of age and sex to allergic rhinitis is not ...comprehensively understood. This study aimed to characterize allergic rhinitis and the associated clinical manifestations by age and sex.
Methods:
We retrospectively investigated data from 2883 patients who visited a single university hospital for rhinitis symptoms between January 2003 and December 2014. Of these 2883 patients, 1964 who underwent a skin prick test with 11 standardized allergen extracts and completed a nasal symptom questionnaire were enrolled. The clinical characteristics of allergen sensitization and nasal symptoms were analyzed by sex and age distribution.
Results:
The prevalence of allergen sensitization progressively decreased with age after peaking at between 20 and 29 years. The sensitization rate was higher in males than in females (P = .046). The sensitization rate to house dust mites decreased with age, while sensitization to mugwort and ragweed increased. Six allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, mugwort, trees, ragweed, and cats) were sufficient to identify >96% of patients with allergen sensitization. Nasal obstruction tended to decrease with age and was more prevalent in males (P = .002) than in females, while rhinorrhea (P = .007) and itching (P = .013) were more prevalent in females. Total nasal symptom scores did not differ by sex.
Conclusions:
The clinical characteristics of allergic rhinitis, including allergen-sensitization patterns and related symptoms, varied by age and sex. Six common allergens could be sufficient to generate a cost-effective tool to identify allergic rhinitis.
Abstract
Dopamine (DA) plays a vital role in brain physiology and pathology such as learning and memory, motor control, neurological diseases, and psychiatric diseases. In neurons, it has been well ...established that DA increases or decreases intracellular cyclic AMP (cAMP) through D
1
-like or D
2
-like dopamine receptors, respectively. In contrast, it has been elusive how astrocytes respond to DA via Ca
2+
signaling and regulate synaptic transmission and reward systems. Previous studies suggest various molecular targets such as MAO-B, D
1
R, or D
1
R–D
2
R heteromer to modulate astrocytic Ca
2+
signaling. However, which molecular target is utilized under what physiological condition remains unclear. Here, we show that DA-induced astrocytic Ca
2+
signaling pathway switches during development: MAO-B is the major player at a young age (5–6 weeks), whereas DA receptors (DARs) are responsible for the adult period (8–12 weeks). DA-mediated Ca
2+
response in the adult period was decreased by either D
1
R or D
2
R blockers, which are primarily known for cyclic AMP signaling (G
s
and G
i
pathway, respectively), suggesting that this Ca
2+
response might be mediated through G
q
pathway by D
1
R–D
2
R heterodimer. Moreover, DAR-mediated Ca
2+
response was not blocked by TTX, implying that this response is not a secondary response caused by neuronal activation. Our study proposes an age-specific molecular target of DA-induced astrocytic Ca
2+
signaling: MAO-B in young mice and DAR in adult mice.
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.
The association between pet sensitization and pet ownership remains unclear. Therefore, we aimed to elucidate the association between pet sensitization and pet ownership by age.
We retrospectively ...reviewed 2,883 patients who visited our allergy clinic for nasal symptoms from January 2003 to December 2014, of whom 1,957 patients with data on skin-prick tests and questionnaire responses were included and divided into adults (age >19 years) and children (age ≤19 years). The association between pet sensitization and pet ownership was evaluated in both groups.
Among children, dog and cat sensitization showed no associations with dog and cat ownership, respectively. However, among adults, dog sensitization was significantly associated with dog ownership (odds ratio OR, 3.283; P<0.001), and cat sensitization with cat ownership (OR, 13.732; P<0.001). After adjustment for age, sex, familial history of allergy, sinusitis, diabetes mellitus, other pet ownership, and non-pet sensitization, significant associations remained between dog sensitization and dog ownership (adjusted OR aOR, 3.881; P<0.001), and between cat sensitization and cat ownership (aOR, 10.804; P<0.001) among adults. Dog ownership did not show any association with allergic rhinitis, asthma, or atopic dermatitis, whereas atopic dermatitis had a significant association with cat ownership in adults (aOR, 4.840; P<0.001).
Pet ownership in adulthood increased the risk of pet sensitization. However, pet ownership was not associated with the prevalence of atopic disorders, regardless of age, except for atopic dermatitis and cat ownership in adults.
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