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ABSTRACT: Immature hippocampal neurons with high input resistances (R(in)) are vulnerable to hyperexcitable or epileptogenic conditions. This phenomenon has been suggested to explain the neuroprotective roles of hyperpolarization-activated cation channels (I(h) channels) to regulate membrane R(in). In the present study, we tried to electrophysiologically clarify the relationship between membrane R(in) and I(h) channels and determine the neuroprotective roles of these channels in development. The CA1 neurons from rats (within 3 postnatal weeks) were classified into two groups based on the onset time (shorter or longer than 20ms) to fire the first action potential (AP) in response to a current injection (100 pA, 800ms). Neurons with a shorter onset time (Short-OsT), exhibited higher R(in), while neurons with longer onset times (Long-OsT) revealed lower R(in). Unexpectedly, Short-OsT neurons with higher R(in) exhibited larger amplitudes of I(h) compared with Long-OsT neurons. Furthermore, the application of temporal depolarization stimulus (TDS, -14mV holding for 150seconds) significantly enhanced suprathreshold excitabilities of repetitive APs in Long-OsT but not Short-OsT neurons, suggesting a protective role of I(h) channels under high R(in) conditions. In the presence of the specific hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker ZD7288, TDS also enhanced the excitability of Short-OsT neurons, suggesting that young CA1 neurons regulate I(h) channel expression for neuroprotective modulation against epileptogenic conditions.
Brain research bulletin 12/2012; · 2.18 Impact Factor
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ABSTRACT: Blocking or regulating K(+) channels is important for investigating neuronal functions in mammalian brains, because voltage-dependent K(+) channels (Kv channels) play roles to regulate membrane excitabilities for synaptic and somatic processings in neurons. Although a number of toxins and chemicals are useful to change gating properties of Kv channels, specific effects of each toxin on a particular Kv subunit have not been sufficiently demonstrated in neurons yet. In this study, we tested electrophysiologically if heteropodatoxin2 (HpTX(2)), known as one of Kv4-specific toxins, might be effective on various K(+) outward currents in CA1 neurons of organotypic hippocampal slices of rats. Using a nucleated-patch technique and a pre-pulse protocol in voltage-clamp mode, total K(+) outward currents recorded in the soma of CA1 neurons were separated into two components, transient and sustained currents. The extracellular application of HpTX(2) weakly but significantly reduced transient currents. However, when HpTX(2) was added to internal solution, the significant reduction of amplitudes were observed in sustained currents but not in transient currents. This indicates the non-specificity of HpTX(2) effects on Kv4 family. Compared with the effect of cytosolic 4-AP to block transient currents, it is possible that cytosolic HpTX(2) is pharmacologically specific to sustained currents in CA1 neurons. These results suggest that distinctive actions of HpTX(2) inside and outside of neurons are very efficient to selectively reduce specific K(+) outward currents.
Korean Journal of Physiology and Pharmacology 10/2012; 16(5):343-8. · 0.96 Impact Factor
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ABSTRACT: Mitochondrial membrane potential (∆Ψ(m) ) contributes to determining a driving force for calcium to enter the mitochondria. It has been demonstrated that even a small mitochondrial depolarization is sufficient to prevent mitochondrial calcium overload and the subsequent apoptosis. Therefore, mild mitochondrial depolarization has been recently evaluated as a novel mechanism of neuroprotection via inhibiting neurotoxic mitochondrial calcium overload during neuronal insults. In the present study, using both real-time recording and flow cytometric analyses of ∆Ψ(m) , we demonstrated that ethanolic peel extract of Citrus sunki Hort. ex Tanaka (CPE) and its active compounds are capable of inducing a mild mitochondrial depolarization. Polymethoxylated flavones such as nobiletin and tangeretin were found as the active compounds responsible for CPE effects on ∆Ψ(m) . Neuronal viability was significantly increased in a dose-dependent manner by CPE treatment in H(2) O(2) -stimulated HT-22 cells as an in vitro neuronal insult model. CPE treatment significantly inhibited H(2) O(2) -induced apoptotic processes such as chromatin condensation, caspase 3 activation and anti-poly (ADP-ribose) polymerase (PARP) cleavage. CPE treatment significantly blocked mitochondrial calcium overload in H(2) O(2) -stimulated HT-22 neurons as indicated by rhod-2 acetoxymethyl ester. Taken together, our findings suggest that CPE and its active compounds may be considered as promising neuroprotective agents via inducing a mild mitochondrial depolarization. Copyright © 2012 John Wiley & Sons, Ltd.
Phytotherapy Research 06/2012; · 2.09 Impact Factor
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ABSTRACT: Excessive microglial activation-mediated neurotoxicity has been implicated in playing a crucial role in the pathogenesis of stroke and neurodegenerative diseases. Therefore, much attention has been paid to therapeutic strategies aimed at suppressing neurotoxic microglial activation. The microglial regulatory mechanism of methyl lucidone, a cyclopentenedione isolated from the stem bark of Lindera erythrocarpa Makino, was investigated in the present study. Methyl lucidone treatment (0.1-10 μM) significantly inhibited lipopolysaccharide (LPS, 100 ng/ml, 24 h)-stimulated nitric oxide (NO) production in a dose-dependent manner in both primary cortical microglia and BV-2 cell line. Moreover, it strongly inhibited LPS-stimulated secretion of pro-inflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α). Methyl lucidone treatment markedly induced down-regulation of LPS-induced nuclear translocation of nuclear factor κB (NF-κB) through preventing the degradation of the inhibitory protein IκBα. In addition, phosphorylation of Akt and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK) and p38 kinases were also suppressed by methyl lucidone. The cell viabilities of HT-22 neurons were significantly attenuated by treatment of the conditioned media containing neurotoxic secretary molecules from LPS-stimulated microglia. However, methyl lucidone significantly blocked neuronal cell death induced by microglial conditioned media. These neuroprotective effects of methyl lucidone were also confirmed in a neuron-microglia co-culture system using EGFP-transfected B35 neuroblastoma cell line. Taken together, these results suggest that methyl lucidone may have a neuroprotective potential via inhibition of neurotoxic microglial activation implicated in neurodegeneration.
European journal of pharmacology 06/2012; 690(1-3):4-12. · 2.59 Impact Factor
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ABSTRACT: Proper expression of synaptic NMDA receptors (NMDARs) is necessary to regulate synaptic Ca²(+) influx and the induction the long-term potentiation (LTP) in the mammalian hippocampus. Previously we reported that expressing the A-type K(+) channel subunit Kv4.2 in CA1 neurons of organotypic slice cultures reduced synaptic NR2B-containing NMDAR expression and completely blocked LTP induced by a pairing protocol. As pretreatment with an NMDAR antagonist (APV) overnight blocked the reduction of NR2B-containing receptors in neurons expressing EGFP-labeled Kv4.2 (Kv4.2g), we hypothesized that LTP would be rescued in Kv4.2g neurons by overnight treatment with APV. We report here that the overnight APV pretreatment in Kv4.2g-expressing neurons only partially restored potentiation. This partial potentiation was completely blocked by inhibition of the CAMKII kinase. These results indicate that A-type K(+) channels must regulate synaptic integration and plasticity through another mechanism in addition to their regulation of synaptic NR2 subunit composition. We suggest that dendritic excitability, which is regulated by Kv4.2 expression, also contributes to synaptic plasticity.
Brain research bulletin 10/2010; 84(1):17-21. · 2.18 Impact Factor
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Yanji Cui,
Jinji Wu, Sung-Cherl Jung,
Deok-Bae Park,
Young-Hee Maeng,
Jeong Yun Hong,
Se-Jae Kim,
Sun-Ryung Lee,
Soon-Jong Kim,
Sang Jeong Kim,
Su-Yong Eun
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ABSTRACT: A growing body of evidence suggests that nobiletin (5,6,7,8,3',4'-hexamethoxy flavone) from the peel of citrus fruits, enhances the damaged cognitive function in disease animal models. However, the neuroprotective mechanism has not been clearly elucidated. Since nobiletin has shown anti-inflammatory effects in several tissues, we investigated whether nobiletin suppresses excessive microglial activation implicated in neurotoxicity in lipopolysaccharide (LPS)-stimulated BV-2 microglia cell culture models. Release of nitric oxide (NO), the major inflammatory mediator in microglia, was markedly suppressed in a dose-dependent manner following nobiletin treatment (1-50 µM) in LPS-stimulated BV-2 microglia cells. The inhibitory effect of nobiletin was similar to that of minocycline, a well-known microglial inactivator. Nobiletin significantly inhibited the release of the pro-inflammatory cytokine tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β). LPS-induced phosphorylations of extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs) were also significantly inhibited by nobiletin treatment. In addition, nobiletin markedly inhibited the LPS-induced pro-inflammatory transcription factor nuclear factor κB (NF-κB) signaling pathway by suppressing nuclear NF-κB translocation from the cytoplasm and subsequent expression of NF-κB in the nucleus. Taken together, these results may contribute to further exploration of the therapeutic potential and molecular mechanism of nobiletin in relation to neuroinflammation and neurodegenerative diseases.
Biological & Pharmaceutical Bulletin 01/2010; 33(11):1814-21. · 1.66 Impact Factor
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ABSTRACT: Since its original description, the induction of synaptic long-term potentiation (LTP) has been known to be accompanied by a lasting increase in the intrinsic excitability (intrinsic plasticity) of hippocampal neurons. Recent evidence shows that dendritic excitability can be enhanced by an activity-dependent decrease in the activity of A-type K(+) channels. In the present manuscript, we examined the role of A-type K(+) channels in regulating intrinsic excitability of CA1 pyramidal neurons of the hippocampus after synapse-specific LTP induction. In electrophysiological recordings we found that LTP induced a potentiation of excitability which was accompanied by a two-phased change in A-type K(+) channel activity recorded in nucleated patches from organotypic slices of rat hippocampus. Induction of LTP resulted in an immediate but short lasting hyperpolarization of the voltage-dependence of steady-state A-type K(+) channel inactivation along with a progressive, long-lasting decrease in peak A-current density. Blocking clathrin-mediated endocytosis prevented the A-current decrease and most measures of intrinsic plasticity. These results suggest that two temporally distinct but overlapping mechanisms of A-channel downregulation together contribute to the plasticity of intrinsic excitability. Finally we show that intrinsic plasticity resulted in a global enhancement of EPSP-spike coupling.
PLoS ONE 02/2009; 4(8):e6549. · 4.09 Impact Factor
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ABSTRACT: The transient, A-type K+ current (IA) controls the excitability of CA1 pyramidal neuron dendrites by regulating the back-propagation of action potentials and by shaping synaptic input. Dendritic A-type K+ channels are targeted for modulation during long-term potentiation (LTP) and we have recently shown that activity-dependent internalization of the A-type channel subunit Kv4.2 enhances synaptic currents. However, the effect of changes in IA on the ability to induce subsequent synaptic plasticity (metaplasticity) has not been investigated. Here, we show that altering functional Kv4.2 expression level leads to a rapid, bidirectional remodeling of CA1 synapses. Neurons exhibiting enhanced IA showed a decrease in relative synaptic NR2B/NR2A subunit composition and did not exhibit LTP. Conversely, reducing IA by expression of a Kv4.2 dominant-negative or through genomic knockout of Kv4.2 led to an increased fraction of synaptic NR2B/NR2A and enhanced LTP. Bidirectional synaptic remodeling was mimicked in experiments manipulating intracellular Ca2+ and dependent on spontaneous activation of NMDA receptors and CaMKII activity. Our data suggest that A-type K+ channels are an integral part of a synaptic complex that regulates Ca2+ signaling through spontaneous NMDAR activation to control synaptic NMDAR expression and plasticity.
Neuron 12/2008; 60(4):657-71. · 14.74 Impact Factor
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ABSTRACT: A-type K+ currents have unique kinetic and voltage-dependent properties that allow them to finely tune synaptic integration, action potential (AP) shape and firing patterns. In hippocampal CA1 pyramidal neurons, Kv4 channels make up the majority of the somatodendritic A-type current. Studies in heterologous expression systems have shown that Kv4 channels interact with transmembrane dipeptidyl-peptidase-like proteins (DPPLs) to regulate the surface trafficking and biophysical properties of Kv4 channels. To investigate the influence of DPPLs in a native system, we conducted voltage-clamp experiments in patches from CA1 pyramidal neurons expressing short-interfering RNA (siRNA) targeting the DPPL variant known to be expressed in hippocampal pyramidal neurons, DPPX (siDPPX). In accordance with heterologous studies, we found that DPPX downregulation in neurons resulted in depolarizing shifts of the steady-state inactivation and activation curves, a shallower conductance-voltage slope, slowed inactivation, and a delayed recovery from inactivation for A-type currents. We carried out current-clamp experiments to determine the physiological effect of the A-type current modifications by DPPX. Neurons expressing siDPPX exhibited a surprisingly large reduction in subthreshold excitability as measured by a decrease in input resistance, delayed time to AP onset, and an increased AP threshold. Suprathreshold DPPX downregulation resulted in slower AP rise and weaker repolarization. Computer simulations supported our experimental results and demonstrated how DPPX remodeling of A-channel properties can result in opposing sub- and suprathreshold effects on excitability. The Kv4 auxiliary subunit DPPX thus acts to increase neuronal responsiveness and enhance signal precision by advancing AP initiation and accelerating both the rise and repolarization of APs.
Journal of Neurophysiology 08/2008; 100(4):1835-47. · 3.32 Impact Factor
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ABSTRACT: Voltage-gated A-type K+ channel Kv4.2 subunits are highly expressed in the dendrites of hippocampal CA1 neurons. However, little is known about the subcellular distribution and trafficking of Kv4.2-containing channels. Here we provide evidence for activity-dependent trafficking of Kv4.2 in hippocampal spines and dendrites. Live imaging and electrophysiological recordings showed that Kv4.2 internalization is induced rapidly upon glutamate receptor stimulation. Kv4.2 internalization was clathrin mediated and required NMDA receptor activation and Ca2+ influx. In dissociated hippocampal neurons, mEPSC amplitude depended on functional Kv4.2 expression level and was enhanced by stimuli that induced Kv4.2 internalization. Long-term potentiation (LTP) induced by brief glycine application resulted in synaptic insertion of GluR1-containing AMPA receptors along with Kv4.2 internalization. We also found evidence of Kv4.2 internalization upon synaptically evoked LTP in CA1 neurons of hippocampal slice cultures. These results present an additional mechanism for synaptic integration and plasticity through the activity-dependent regulation of Kv4.2 channel surface expression.
Neuron 07/2007; 54(6):933-47. · 14.74 Impact Factor
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ABSTRACT: Experimentally induced heterotopia exhibit many of the anatomical features characteristic of cortical malformations in children with early-onset epilepsy. We used extracellular field potential recordings from the dorsal hippocampus of intact adult rats to determine whether the excitability of CA1 pyramidal cells was enhanced in rats with experimentally induced hippocampal dysplasia. Electrical stimulation of afferent fibers resulted in more robust population responses in the CA1 region of methylazoxymethanol (MAM)-treated rats vs the controls. The local population of CA1 pyramidal neurons was more excitable in the MAM-treated rat than in the control animals after synaptic activation. These results suggest that the excitability of the CA1 region in rats with hippocampal dysplasia is greater than that in control animals.
Neuroreport 08/2004; 15(10):1639-42. · 1.66 Impact Factor
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ABSTRACT: Spontaneous activities of single cells were extracellularly recorded in ventral posterior medial (VPM) thalamus of anesthetized rats to characterize the corticothalamic modulation on formalin-induced changes of spontaneous thalamic firing. Formalin injected into the peripheral receptive field, dose-dependently induced the reversible facilitation of spontaneous activities of VPM. However, when the primary somatosensory (SI) cortex was inactivated by muscimol, the pattern of formalin-induced changes of VPM firing was altered. This altered responsiveness included both first and second phase of facilitated spontaneous activities. Bicuculline infused into SI cortex did not alter the pattern of formalin-induced thalamic changes. These results suggest that the pain reactivity of VPM thalamus may be modulated by cortex via corticothalamic pathway during the generation of inflammatory pain.
Neuroreport 07/2004; 15(9):1405-8. · 1.66 Impact Factor
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ABSTRACT: Effects of hypothermia on the afferent somatosensory transmission to the ventroposteromedial (VPM) thalamus were determined in anesthetized rats and hamsters. Hamsters showed a gradual suppression of afferent sensory transmission during cooling (to 18 degrees C) and disinhibition during subsequent warming of body temperature (Tb). However, rats exhibited steep inhibition from Tb 26 degrees C to complete absence of sensory transmission at Tb 20 degrees C and abrupt disinhibition during subsequent warming. Species difference at thalamic level was quite similar to our previous results in the primary somatosensory (SI) cortex, suggesting that changes of sensory transmission observed in the SI cortex may have already occurred at thalamic level. Differences between the cortex and the thalamus were observed only during deep hypothermia in rat and during the final period of warming in hamster. Conduction latencies of thalamocortical system of both species were not influenced during Tb lowering until 24 degrees C (equivalent to brain temperature 25-26 degrees C). These results suggest inherently different adaptability to hypothermia in processing somatosensory information between hibernator and non-hibernator, but similar sustainability of sensory functions of the thalamocortical system during hypothermia in both species.
Brain Research 05/2004; 1003(1-2):122-9. · 2.73 Impact Factor
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ABSTRACT: Single neurons were simultaneously recorded in the primary somatosensory (SI) cortex of rats to characterize the effects of applied bicuculline on the temporary deafferentation (TD)-induced plasticity. In the absence of TD, bicuculline application caused TD-like plasticity such as the expansion of receptive field (RF) and facilitation of sensory transmission in RF boundary cell. It also induced the originally unresponsive neurons to be responsive to the peripheral stimulation. In RF center neurons, TD-induced suppression of sensory transmission was not changed by bicuculline. However, TD-induced facilitation of sensory transmission to the RF boundary neuron was not observed in the presence of bicuculline. These results provide clear evidence that TD-induced plasticity in the SI cortex is mediated by the reversible suppression of lateral inhibition by GABAergic neurons.
Neuroscience Letters 01/2003; 334(2):87-90. · 2.11 Impact Factor
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ABSTRACT: Many single neurons were simultaneously recorded from forepaw areas of both primary somatosensory cortex and the ventral posterior lateral thalamus of anesthetized rats to characterize the changes of presumable excitatory synaptic connections between two nuclei following temporary deafferentation (TD). Thalamic and cortical interactions were examined by analyzing spike-triggered cross-correlation histograms (STCCHs, n=426). Before TD, 46.48% of STCCHs exhibited thalamocortical (TC) excitation and 7.51% of STCCHs showed corticothalamic (CT) connectivity. After TD, these connections were less frequently observed (after 20 min of TD, TC: 13.38% of STCCHs, CT: 5.40% of STCCHs). Fifty-seven TC and nine CT connections were reversibly suppressed during TD. However, 23 CT connections were reversibly augmented following TD. These results imply that temporary blocking of afferent information may induce system-wide plasticity involving corticofugal modulation.
Neuroscience Letters 11/2002; 331(2):111-4. · 2.11 Impact Factor
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ABSTRACT: We observed the changes of body temperature and the cytokine expressions in the hypothalamus of rats to investigate the effect and mechanism of antipyretic action of acupuncture. Lipopolysaccharide (LPS, i.p., 2.5 mg/kg) was injected into rats and manual acupuncture was performed on Shaofu (HT8), Zutonggu (BL66) or Xingjian (LR2), respectively. The results showed that fever induced by LPS-injection was recovered significantly by acupuncture on each acupoint. LPS increased hypothalamic mRNA levels of interleukin-6 and interleukin-1 beta which, on the contrary, were also reduced to normal levels by acupuncture stimulation on BL66. These results suggest that the acupuncture stimulation may be effective for reducing elevated body temperature induced by bacterial inflammation, and part of its action may be mediated through the suppression of hypothalamic production of pro-inflammatory cytokines.
Neuroscience Letters 03/2002; 319(1):45-8. · 2.11 Impact Factor
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ABSTRACT: We observed the changes of body temperature and the cytokine expressions in the hypothalamus of rats to investigate the effect and mechanism of antipyretic action of acupuncture. Lipopolysaccharide (LPS, i.p., 2.5 mg/kg) was injected into rats and manual acupuncture was performed on Shaofu (HT8), Zutonggu (BL66) or Xingjian (LR2), respectively. The results showed that fever induced by LPS-injection was recovered significantly by acupuncture on each acupoint. LPS increased hypothalamic mRNA levels of interleukin-6 and interleukin-1β which, on the contrary, were also reduced to normal levels by acupuncture stimulation on BL66. These results suggest that the acupuncture stimulation may be effective for reducing elevated body temperature induced by bacterial inflammation, and part of its action may be mediated through the suppression of hypothalamic production of pro-inflammatory cytokines.
Neuroscience Letters.
