Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

The number of synaptic vesicles released during fast release plays a major role in determining the strength of postsynaptic response. However, it remains unresolved how the number of vesicles released in response to action potentials is controlled at a single synapse. Recent findings suggest that the Cav2.1 subtype (P/Q-type) of voltage-gated calcium channels is responsible for inducing presynaptic multivesicular release (MVR) at rat cerebellar glutamatergic synapses from granule cells to molecular layer interneurons. The topographical distance from Cav2.1 channels to exocytotic Ca(2+) sensors is a critical determinant of MVR. In physiological trains of presynaptic neurons, MVR significantly impacts the excitability of postsynaptic neurons, not only by increasing peak amplitude but also by prolonging decay time of the postsynaptic currents. Therefore, MVR contributes additional complexity to neural encoding and processing in the cerebellar cortex.

DOI： 10.1007/s12311-015-0677-5

Web of Science

PubMed

researchmap

Other Link： http://link.springer.com/article/10.1007/s12311-015-0677-5/fulltext.html

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for the Advancement of Science (AAAS)  

DOI： 10.1126/science.aaa1299

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry (RSC)  

DOI： 10.1039/c3cc49543d

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.mimet.2012.09.033

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

A simple form of presynaptic plasticity, paired-pulse facilitation (PPF), has been explained as a transient increase in the probability of vesicular release. Using the whole-cell patch-clamp technique to record synaptic activity in rat cerebellar slices, we found different forms of presynaptically originated short-term plasticity during glutamatergic excitatory neurotransmission from granule cells (GCs) to molecular-layer interneurones (INs). Paired-pulse activation of GC axons at short intervals (30-100 ms) elicited not only a facilitation in the peak amplitude (PPF(amp)), but also a prolongation in the decay-time constant (PPP(decay)) of the EPSCs recorded from INs. The results of pharmacological tests and kinetics analyses suggest that the mechanisms underlying the respective types of short-term plasticity were different. PPF(amp) was elicited by a transient increase in the number of released vesicles. On the other hand, PPP(decay) was caused not only by delayed release as has been reported but also by extrasynaptic spillover of the GC transmitter and the subsequent intersynaptic pooling. Both PPF(amp) and PPP(decay) closely rely on repetitive-activation-induced multivesicular release. Using a dynamic clamp technique, we further examined the physiological significance of different presynaptic plasticity, and found that PPF(amp) and PPP(decay) can differentially encode and process neuronal information by influencing the total synaptic charge transferred to postsynaptic INs to reflect activation frequency of the presynaptic GCs.

DOI： 10.1113/jphysiol.2012.234070

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/j.1751-1097.2012.01080.x

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Physiological Society  

Absence seizures consist of a brief and sudden impairment of consciousness. They are characterized by bilaterally synchronized spike and wave discharges (SWDs), which reflect abnormal oscillations in the thalamocortical loops. Recent studies have suggested that the basal ganglia are involved in generation of the SWDs, but their roles are poorly understood at the molecular and cellular levels. Here we studied the pathophysiological roles of the basal ganglia, using in vivo and in vitro measurements of tottering mice, a well-established model of absence epilepsy. We found that the membrane excitability in subthalamic nucleus (STN) neurons was enhanced in tottering mice, which resulted from reduced hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity. Pharmacological blockade and activation of HCN channel activity in vitro bidirectionally altered the membrane excitability of the STN neurons. Furthermore, these pharmacological modulations of HCN channel activity in the STN in vivo bidirectionally altered the mean SWD duration. In addition, STN deep brain stimulation modulated SWDs in a frequency-dependent manner. These results indicate that STN is involved in the rhythm maintenance system of absence seizures.

DOI： 10.1152/jn.00937.2010

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>
<sec>
<title>Background</title>
One of the best-characterized causative factors of Alzheimer’s disease (AD) is the generation of amyloid-β peptide (Aβ). AD subjects are at high risk of epileptic seizures accompanied by aberrant neuronal excitability, which in itself enhances Aβ generation. However, the molecular linkage between epileptic seizures and Aβ generation in AD remains unclear.


</sec>
<sec>
<title>Results</title>
X11 and X11-like (X11L) gene knockout mice suffered from epileptic seizures, along with a malfunction of hyperpolarization-activated cyclic nucleotide gated (HCN) channels. Genetic ablation of HCN1 in mice and HCN1 channel blockage in cultured Neuro2a (N2a) cells enhanced Aβ generation. Interestingly, HCN1 levels dramatically decreased in the temporal lobe of cynomolgus monkeys (<italic>Macaca fascicularis</italic>) during aging and were significantly diminished in the temporal lobe of sporadic AD patients.


</sec>
<sec>
<title>Conclusion</title>
Because HCN1 associates with amyloid-β precursor protein (APP) and X11/X11L in the brain, genetic deficiency of X11/X11L may induce aberrant HCN1 distribution along with epilepsy. Moreover, the reduction in HCN1 levels in aged primates may contribute to augmented Aβ generation. Taken together, HCN1 is proposed to play an important role in the molecular linkage between epileptic seizures and Aβ generation, and in the aggravation of sporadic AD.


</sec>

DOI： 10.1186/1750-1326-7-50

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.bbamem.2010.10.007

Web of Science

CiNii Article

CiNii Books

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry (RSC)  

DOI： 10.1039/c0pp00376j

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Fasting has been used to control epilepsy since antiquity, but the mechanism of coupling between metabolic state and excitatory neurotransmission remains unknown. Previous work has shown that the vesicular glutamate transporters (VGLUTs) required for exocytotic release of glutamate undergo an unusual form of regulation by Cl(-). Using functional reconstitution of the purified VGLUTs into proteoliposomes, we now show that Cl(-) acts as an allosteric activator, and the ketone bodies that increase with fasting inhibit glutamate release by competing with Cl(-) at the site of allosteric regulation. Consistent with these observations, acetoacetate reduced quantal size at hippocampal synapses and suppresses glutamate release and seizures evoked with 4-aminopyridine in the brain. The results indicate an unsuspected link between metabolic state and excitatory neurotransmission through anion-dependent regulation of VGLUT activity.

DOI： 10.1016/j.neuron.2010.09.002

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Society for Analytical Chemistry  

The photodynamic inactivation of the membrane functions of bacteria was analyzed in situ, using K⁺ and tetraphenylphosphonium (TPP⁺) electrodes, as well as an oxygen electrode. Tetrakis(4-N-trimethylaminophenyl)porphine (TTMAPP) and rose bengal were used, since both dyes act strongly on bacteria, such as Staphylococcus aureus. After a short time lag, they inhibited the respiration of bacteria and increased the permeability of the cytoplasmic membrane to K⁺, while dissipating the membrane potential. This combination of sensors is quite useful for visualizing the actions of photosensitizers on the bacterial membrane. TTMAPP and rose bengal impaired the bacterial function by reducing the membrane potential within minutes of photo-irradiation.

DOI： 10.2116/analsci.26.1019

Web of Science

CiNii Article

CiNii Books

researchmap

Other Link： https://jlc.jst.go.jp/DN/JALC/00357148981?from=CiNii

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Society for Analytical Chemistry  

The ability to scavenge superoxide anion radicals (^•O₂⁻) was determined using an oxygen electrode. The method is based on the determination of ^•O₂⁻ generated by the reaction of nitrilotriacetatoiron(III) with hydrogen peroxide and a decrease in the concentration of ^•O₂⁻ by a scavenging reaction, converting into a change in the generation of oxygen molecules through an electron-transfer reaction from ^•O₂⁻ to nitrilotriacetatoiron(III). Oxygen generation, which enhanced proportionally with an increase in the concentration of hydrogen peroxide, was inhibited depending on the concentration of superoxide dismutase. Hence, we applied the present reaction system to evaluate the ^•O₂⁻-scavenging abilities of an antioxidant, measuring the degree of inhibition of oxygen generation using an oxygen electrode. A good correlation was obtained between the present method and conventional colorimetry, monitoring the formation of blueformazan by the reaction of nitro blue tetrazolium with ^•O₂⁻, to estimate the ^•O₂⁻-scavenging activities of antioxidants.

DOI： 10.2116/analsci.26.903

Web of Science

CiNii Article

CiNii Books

researchmap

Other Link： https://jlc.jst.go.jp/DN/JALC/00354523491?from=CiNii

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Hypothalamic neurons containing orexin (hypocretin) are activated during motivated behaviors and active waking. We show that injection of orexin-A into the ventromedial hypothalamus (VMH) of mice or rats increased glucose uptake and promoted insulin-induced glucose uptake and glycogen synthesis in skeletal muscle, but not in white adipose tissue, by activating the sympathetic nervous system. These effects of orexin were blunted in mice lacking beta-adrenergic receptors but were restored by forced expression of the beta(2)-adrenergic receptor in both myocytes and nonmyocyte cells of skeletal muscle. Orexin neurons are activated by conditioned sweet tasting and directly excite VMH neurons, thereby increasing muscle glucose metabolism and its insulin sensitivity. Orexin and its receptor in VMH thus play a key role in the regulation of muscle glucose metabolism associated with highly motivated behavior by activating muscle sympathetic nerves and beta(2)-adrenergic signaling.

DOI： 10.1016/j.cmet.2009.09.013

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Physiological Society  

Little is known about the cellular mechanisms that underlie the processing and storage of sensory in the mammalian olfactory system. Here we show that persistent spiking, an activity pattern associated with working memory in other brain regions, can be evoked in the olfactory bulb by stimuli that mimic physiological patterns of synaptic input. We find that brief discharges trigger persistent activity in individual interneurons that receive slow, subthreshold oscillatory input in acute rat olfactory bulb slices. A 2- to 5-Hz oscillatory input, which resembles the synaptic drive that the olfactory bulb receives during sniffing, is required to maintain persistent firing. Persistent activity depends on muscarinic receptor activation and results from interactions between calcium-dependent afterdepolarizations and low-threshold Ca spikes in granule cells. Computer simulations suggest that intrinsically generated persistent activity in granule cells can evoke correlated spiking in reciprocally connected mitral cells. The interaction between the intrinsic currents present in reciprocally connected olfactory bulb neurons constitutes a novel mechanism for synchronized firing in subpopulations of neurons during olfactory processing.

DOI： 10.1152/jn.00526.2007

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Society for Analytical Chemistry  

DOI： 10.2116/analsci.24.1551

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Society for Neuroscience  

DOI： 10.1523/jneurosci.2961-07.2007

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Physiological Society  

Thalamocortical (TC) cells in the ventrobasal thalamus make direct excitatory connections with regular-spiking (RS) cells in layer 4 of the somatosensory cortex, but also make disynaptic feedforward inhibitory connections with the RS cells by layer 4 fast-spiking (FS) cells. In this study, we investigated connection rules of the feedforward inhibitory circuit from multiple TC cells to multiple RS cells, at the level of synaptic potentials. Using thalamocortical brain slices of young mice (postnatal days 12–16), we made simultaneous patch-clamp recordings from three adjacent cortical cells (two RS cells and one FS cell), combined with minimal stimulation of presumed single TC fibers. We found that nearly all (97%) of TC fibers, which generated excitatory inputs onto RS cells, also generated divergent excitatory inputs onto adjacent FS cells. Some 44% of TC fibers generated divergent excitatory inputs onto adjacent pairs of RS cells. We then combined the triple patch-clamp recording with multisite (two to three) minimal stimulation of single TC fibers and found that 86% of FS cells received convergent inputs from all of the stimulated TC fibers. We also found that 68% of FS cells generated divergent inhibitory inputs onto adjacent pairs of RS cells. The results indicate that spikes in TC cells, which excite RS cells, also excite adjacent FS cells with high fidelity. The results also indicate that FS cells receive convergent excitatory inputs from multiple TC cells and then send divergent inhibitory outputs to multiple RS cells.

DOI： 10.1152/jn.00301.2006

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Physiological Society  

We developed an in vitro odor-aversion conditioning system in the terrestrial mollusk, Limax, and found a behavioral correlate of network oscillation in the olfactory CNS. We first examined the odor-induced behavior of Limax, after odor-aversion conditioning in vivo. Shortening of mantle muscles was specifically observed in response to aversively conditioned odors. We previously identified that parietal nerves, which project to the mantle muscle in Limax, regulate shortening of the mantle muscle. We therefore isolated whole brains containing noses (sensory organs) and parietal nerves (motor output), and applied an odor-aversion conditioning paradigm to these in vitro preparations. Before the in vitro conditioning, application of attractive odors to the noses did not elicit any discharge in the parietal nerves. However, after odor-aversion conditioning, discharges in the parietal nerves were observed in response to the natively attractive but aversively conditioned odors. We also found that network oscillation frequency in the procerebrum (PC), the olfactory CNS of Limax, increased specifically in response to the aversively conditioned odors that elicited avoidance behavior. In naive (nonconditioned) preparations, increases in the PC oscillation frequency were observed specifically in response to innately aversive odors. These results indicate that the isolated brains have an ability of odor learning. They also suggest that changes in PC network oscillation are associated with aversively conditioned and innately aversive odors, both of which elicit avoidance behavior. This in vitro conditioning system would be an effective approach for exploring the neural mechanism to determine the aversion to odors.

DOI： 10.1152/jn.00853.2005

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Society for Neuroscience  

The tottering (tg) mice have a mutation in the CaV2.1 (P/Q-type) voltage-dependent Ca2+ channel alpha(1)2.1 subunit gene. tg mice show not only cerebellar ataxia but also absence epilepsy, which begins at approximately 3 weeks of age and persists throughout life. Similarities in EEG and sensitivity to antiepileptic drugs suggest that tg mice are a good model for human absence epilepsy. Although imbalance between excitatory and inhibitory activity in the thalamocortical network is thought to contribute to the pathogenesis of absence epilepsy, the effect of the mutation on thalamocortical synaptic responses remains unknown. Here we showed imbalanced impairment of inhibitory synaptic responses in tg mice using brain slice preparations. Somatosensory thalamocortical projection makes not only monosynaptic glutamatergic connections but also disynaptic GABAergic connections, which mediate feedforward inhibition, onto layer IV neurons. In tg mice, IPSC amplitudes recorded from layer IV pyramidal cells of the somatosensory cortex in response to thalamic stimulation became disproportionately reduced compared with EPSC amplitudes at later developmental stages (postnatal days 21-30). Similar results were obtained by local stimulation of layer IV pyramidal neurons. However, IPSC reduction was not seen in layer V pyramidal neurons of epileptic tg mice or in layer IV pyramidal neurons of younger tg mice before the onset of epilepsy (postnatal days 14-16). These results showed that the feedforward inhibition from the thalamus to layer IV neurons of the somatosensory cortex was severely impaired in tg mice and that the impairment of the inhibitory synaptic transmission was correlated to the onset of absence epilepsy.

DOI： 10.1523/jneurosci.5422-05.2006

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

DOI： 10.1093/chemse/bjh160

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/neu.10295

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Physiological Society  

To explore neural mechanisms how olfactory information is processed in the brain and finally converted into behavior, it would be useful to have isolated whole brains that include both olfactory organs and motor output. In the present study, we identified an in vitro index of odor-evoked behavior in the terrestrial mollusk Limax and also studied the modulation of this in vitro index of the behavior. We determined that shortening of the mantle muscles is one of the withdrawal responses selectively induced by aversive odors and that the shortening is mediated by a pair of parietal nerves. We also identified a motoneuron (named the posterior visceral neuron, p-VN) that projects to the parietal nerve and innervates the mantle muscles. When we applied various odors to the nose in these isolated molluscan brains, only aversive odors induced discharges in the p-VN. These results indicate that p-VN discharges can serve as an in vitro index of odor-induced aversive behavior. We also identified a novel serotonergic neuron (named the posterior cerebral serotonergic cell, p-CSC). Discharges in the p-CSC released serotonin to the tentacle ganglion (TG); serotonin in the TG then inhibited odor-induced discharges in the p-VN, the in vitro index of aversive behavior. These results suggest that the serotonergic system is involved in the regulation of approach and avoidance behavior in Limax.

DOI： 10.1152/jn.00247.2003

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Society for Neuroscience  

DOI： 10.1523/jneurosci.23-07-02932.2003

Web of Science

CiNii Article

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Physiological Society  

We identified two classes of network oscillations with different frequency ranges in the tentacle ganglion (TG), the primary olfactory center of the terrestrial mollusk Limax marginatus, and investigated the responses of these oscillations to odor inputs. A recent study indicated that there are serotonergic terminals in the TG. We found that when serotonin was applied to the TG, the spontaneous network oscillation of about 1.5 Hz in the TG changed its oscillatory frequency to 0.5 Hz. These two oscillations are distinct, because 1) in most cases, the application of serotonin to the TG initially inhibited the 1.5-Hz oscillation and subsequently generated the slow 0.5-Hz oscillation; and 2) occasionally, the application of serotonin did not inhibit the spontaneous 1.5-Hz oscillation, resulting in the coexistence of two network oscillations. Thus the TG has two different oscillatory dynamics. We named the spontaneous 1.5-Hz oscillation the fast oscillation (FO), and the serotonin-induced 0.5-Hz oscillation the slow oscillation (SO). By calculating the spatial coherence of the TG oscillations, we found that the FO is a noncoherent oscillatory mode and the SO is a coherent oscillatory mode. Finally, odor presentation to the olfactory receptors selectively modulated the SO by decreasing the oscillatory amplitude, but the FO was not modulated by the odor input. These results indicate that 1) the TG has two oscillatory states (FO and SO) and these states are changed by the extracellular level of serotonin, and 2) these two oscillatory states have different responses to odors.

DOI： 10.1152/jn.2002.87.6.3160

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/s0006-8993(01)03096-7

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Physiological Society  

Synchronous oscillation of membrane potentials, generated by assemblies of neurons, is a prominent feature in the olfactory systems of many vertebrate and invertebrate species. However, its generation mechanism is still controversial. Biogenic amines play important roles for mammalian olfactory learning and are also implicated in molluscan olfactory learning. Here, we investigated the role of serotonin, a biogenic amine, in the oscillatory dynamics in the procerebrum (PC), the molluscan olfactory center. Serotonin receptor blockers inhibited the spontaneous synchronous oscillatory activity of low frequency (approximately 0.5 Hz) in the PC. This was due to diminishing the periodic slow oscillation of membrane potential in bursting (B) neurons, which are essential neuronal elements for the synchronous oscillation in the PC. On the other hand, serotonin enhanced the amplitude of the slow oscillation in B neurons and subsequently increased the number of spikes in each oscillatory cycle. These results show that the extracellular serotonin level regulates the oscillation amplitude in B neurons and thus serotonin may be called an oscillation generator in the PC. Although nitric oxide (NO) is known to also be a crucial factor for generating the PC oscillatory activity and setting the PC oscillation frequency, the present study showed that NO only regulates the oscillation frequency in B neurons but could not increase the spikes in each oscillatory cycle. These results suggest complementary regulation of the PC oscillatory activity: NO determines the probability of occurrence of slow potentials in B neurons, whereas serotonin regulates the amplitude in each cycle of the oscillatory activity in B neurons.

DOI： 10.1152/jn.2001.85.6.2634

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/s0006-8993(00)03242-x

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Physiological Society  

With electrophysiological techniques, we found phase-dependent modification of the efficacy of signal transmission in the procerebrum (PC), the oscillatory olfactory center, of the terrestrial mollusk Limax marginatus and elucidated its neuronal mechanism. Previous studies have indicated that about 10⁵ PC neurons can be classified into only two types: bursting (B) neurons and nonbursting (NB) neurons, and both types of neurons have ongoing and phase-locked periodic oscillation of their membrane potentials. On olfactory nerve stimulation, excitatory postsynaptic potentials (EPSPs) were evoked with a constant latency in NB neurons, while EPSPs with a variable latency were evoked in B neurons. These findings suggest a monosynaptic connection from the olfactory nerve to NB neurons, but a polysynaptic connection between the olfactory nerve and B neurons. This polysynaptic transmission is most likely mediated by NB neurons because the olfactory nerve makes synaptic connection only with NB neurons in the PC. The latency of the evoked EPSPs in B neurons depended on the phase of the PC oscillatory activity, presumably because of the oscillation of the intervening NB neurons. These results suggest that the efficacy of olfactory nerve–B neuron polysynaptic transmission is regulated by the activity level of the phasically oscillating NB neurons. Thus, the intrinsic oscillation in the PC can serve as a filter for olfactory information conveyed from the olfactory nerve as a train of neuronal spikes. This filtering system may also produce a phase-dependent modification by the olfactory input of the PC oscillation frequency.

DOI： 10.1152/jn.2000.84.2.1112

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE LTD  

Multiple cerebral infarctions were observed in a patient with refractory idiopathic thrombocytopenic purpura who was positive for lupus anticoagulant (LAC) when her platelet counts were 2000 mu L(-1). It is suspected that LAC may have played an important role in the pathogenesis of this patient's cerebral infarctions, although she had severe thrombocytopenia.

Web of Science

researchmap

researchmap

Language：Japanese   Publisher：The Biophysical Society of Japan General Incorporated Association  

DOI： 10.2142/biophys.56.030

CiNii Article

CiNii Books

researchmap

Other Link： https://jlc.jst.go.jp/DN/JLC/20019937029?from=CiNii

researchmap

researchmap

researchmap

Publisher：Japan Society for Analytical Chemistry  

DOI： 10.2116/bunsekikagaku.62.121

researchmap

researchmap

Language：Japanese   Publisher：The Biophysical Society of Japan General Incorporated Association  

DOI： 10.2142/biophys.39.S64_3

CiNii Article

CiNii Books

researchmap