Biphasic Somatic A-Type K+ Channel Downregulation Mediates Intrinsic Plasticity in Hippocampal CA1 Pyramidal Neurons

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

A Micromachined Silicon Depth Probe for Multichannel Neural Recording

Aprocess of making a new type of silicon depth-probe microelectrode array is described using a combination of plasma and wet etch. The plasma etch, which is done using a low temperature oxide (LTO) mask, enables probe thickness to be controlled over a range from 5 to 90 . Bending tests show that the probes mechanical strength depends largely on shank thickness. More force can be applied to thicker shanks while thinner shanks are more flexible. One can then choose a thickness and corresponding mechanical strength using the process developed. The entire probe shaping process is performed only at low temperature, and thus is consistent with the standard CMOS fabrication. Using the probe in recording from rats somatosensory cortex, we obtained four channel simultaneous recordings which showed clear independence among channels with a signal-to-noise ratio performance comparable with that obtained using other devices.This paper was supported by the Nano Bioelectronics & System Center, Basic Research program of Korea Science and Engineering Foundation (KOSEF) under Grant 971- 0913-076-2, by the Korea Research Foundation (NDRF) under Grant 1996-012- E0529, by Ministry Health andWelfare, Korea under Grant HMP-98-E-1-0006, by the Korea Electronic Technology Institute (KETI) MEMS, and by the Research Products Sharing Program of Inter-university Semiconductor Research Center (ISRC) at Seoul National University

A standardized pathology report for gastric cancer: 2nd edition

The first edition of ‘A Standardized Pathology Report for Gastric Cancer’ was initiated by the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists and published 17 years ago. Since then, significant advances have been made in the pathologic diagnosis, molecular genetics, and management of gastric cancer (GC). To reflect those changes, a committee for publishing a second edition of the report was formed within the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. This second edition consists of two parts: standard data elements and conditional data elements. The standard data elements contain the basic pathologic findings and items necessary to predict the prognosis of GC patients, and they are adequate for routine surgical pathology service. Other diagnostic and prognostic factors relevant to adjuvant therapy, including molecular biomarkers, are classified as conditional data elements to allow each pathologist to selectively choose items appropriate to the environment in their institution. We trust that the standardized pathology report will be helpful for GC diagnosis and facilitate large-scale multidisciplinary collaborative studies

Regulation of Dendritic Excitability by Activity-Dependent Trafficking of the A-Type K+ Channel Subunit Kv4.2 in Hippocampal Neurons

SummaryVoltage-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

Effects of compression/stretching of the spermatic cord and blunt dissection on testicular growth and fertility

Purpose: This study was performed to investigate whether compression/stretching of the spermatic cord or blunt dissection influences testicular development and fertility. In addition, the authors evaluated whether the extents of testicular damage differ between these 2 surgical manipulations. Methods: Forty-four prepubertal male Sprague-Dawley (SD) rats (Harlan Sprague-Dawley Inc, Indianapolis, Ind) were divided into 3 groups: (1) the control group (CG) animals underwent a sham operation in the right groin, (2) the experimental group 1 (EG1) underwent compression/stretching of the right spermatic cord, and (3) the experimental group 2 (EG2) underwent dissection around the right spermatic cord structures. Testicular volumes, weights, mean seminiferous tubular diameters (MSTDs), mean testicular biopsy scores, and numbers of offspring and of pregnant females were evaluated. Results: Right (operative) and left (nonoperative) testicular volumes were smaller in the EG2 group than in the CG or EG1 groups. Left MSTDs in the EG1 and EG2 groups increased more than in the CG group. Numbers of Sertoli cells in left testes differed in the 3 groups, in the order EG1 < CG < EG2. Mean testicular biopsy scores, offspring numbers, and pregnant female numbers were no different in the 3 groups. Conclusions: Both surgical manipulations influenced testicular growth, but they did not compromise spermatogenesis or fertility in SD rats. (C) 2009 Elsevier Inc. All rights reserved.Stegani MM, 2008, J PEDIATR SURG, V43, P1705, DOI 10.1016/j.jpedsurg.2008.01.027Pham SBT, 2005, PEDIATR SURG INT, V21, P231, DOI 10.1007/s00383-005-1364-2Huleihel M, 2004, ASIAN J ANDROL, V6, P259Dufour JM, 2002, J ANDROL, V23, P635Nambirajan L, 2002, PEDIATR SURG INT, V18, P276, DOI 10.1007/s003830100684Crosby LM, 2000, TOXICOL PATHOL, V28, P253Lee SL, 2000, J PEDIATR SURG, V35, P327WEBER TR, 2000, PEDIAT SURG, P654Rey R, 1999, HISTOL HISTOPATHOL, V14, P991Nguyen L, 1999, J PEDIATR SURG, V34, P680LIOYD DA, 1998, PEDIAT SURG, P1071Hadziselimovic F, 1997, LANCET, V350, P118SANDHU DPS, 1991, BRIT J UROL, V68, P513TANYEL FC, 1991, J PEDIATR SURG, V26, P204DEROOIJ DG, 1989, ANN NY ACAD SCI, V564, P140SALMAN FT, 1988, J PEDIATR SURG, V23, P439GAYTAN F, 1986, J ANAT, V145, P155COSENTINO MJ, 1985, J UROLOGY, V133, P906JANIK JS, 1982, J PEDIATR SURG, V17, P585SHANDLING B, 1981, J PEDIATR SURG, V16, P461SKAKKEBA.NE, 1973, J REPROD FERTIL, V32, P379JOHNSEN SG, 1970, HORMONES, V1, P2

Kv4 Accessory Protein DPPX (DPP6) is a Critical Regulator of Membrane Excitability in Hippocampal CA1 Pyramidal Neurons

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

Anti-neuroinflammatory Activity of Nobiletin on Suppression of Microglial Activation

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 mu M) 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-alpha) and interleukin-1 beta (IL-1 beta). 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 kappa B (NF-kappa B) signaling pathway by suppressing nuclear NF-kappa B translocation from the cytoplasm and subsequent expression of NF-kappa B 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.Yrjanheikki J, 1999, P NATL ACAD SCI USA, V96, P13496Rupalla K, 1998, ACTA NEUROPATHOL, V96, P172Zhang ZG, 1997, BRAIN RES, V744, P189BREITNER JCS, 1994, NEUROLOGY, V44, P227Caudle WM, 2009, EXP NEUROL, V220, P230, DOI 10.1016/j.expneurol.2009.09.027Van Damme P, 2009, CURR OPIN NEUROL, V22, P486, DOI 10.1097/WCO.0b013e32832ffbe3Breitner JCS, 2009, NEUROLOGY, V72, P1899, DOI 10.1212/WNL.0b013e3181a18691Min SS, 2009, NEUROSCI LETT, V456, P20, DOI 10.1016/j.neulet.2009.03.079Matsuzaki K, 2008, EUR J PHARMACOL, V578, P194, DOI 10.1016/j.ejphar.2007.09.028Kaushal V, 2008, J NEUROSCI, V28, P2221, DOI 10.1523/JNEUROSCI.5643-07.2008Parameshwaran K, 2008, EXP NEUROL, V210, P7, DOI 10.1016/j.expneurol.2007.10.008Onozuka H, 2008, J PHARMACOL EXP THER, V326, P739, DOI 10.1124/jpet.108.140293Cho IH, 2008, BRAIN, V131, P3019, DOI 10.1093/brain/awn230LU L, 2009, CNS NEUROL DISORD-DR, V9, P232Wang LQ, 2009, TRIBOL T, V52, P59, DOI 10.1109/CCCM.2009.5267991Kim HS, 2009, BEHAV BRAIN RES, V196, P168, DOI 10.1016/j.bbr.2008.09.040Min SS, 2009, BIOCHEM BIOPH RES CO, V383, P93, DOI 10.1016/j.bbrc.2009.03.133Ryu J, 2000, J BIOL CHEM, V275, P29955Combs CK, 2001, J NEUROSCI, V21, P1179Tikka T, 2001, J NEUROSCI, V21, P2580in `t Veld BA, 2001, NEW ENGL J MED, V345, P1515, DOI 10.1056/NEJMoa010178Choi SH, 2003, J NEUROSCI, V23, P5877Szekely CA, 2004, NEUROEPIDEMIOLOGY, V23, P159, DOI 10.1159/000078501ROSI S, 2004, J NEUROINFLAMM, V1, P12Min KJ, 2004, GLIA, V48, P197, DOI 10.1002/glia.20069Eun SY, 2004, BIOCHEM BIOPH RES CO, V325, P320, DOI 10.1016/j.bbrc.2004.10.035Ochfeld E, 2010, STROKE, V41, P325, DOI 10.1161/STROKEAHA.109.570374Ock J, 2010, BIOCHEM PHARMACOL, V79, P596, DOI 10.1016/j.bcp.2009.09.026Pyo H, 1999, J BIOL CHEM, V274, P34584Combs CK, 2000, J NEUROSCI, V20, P558Wu CK, 2005, EXP NEUROL, V195, P484, DOI 10.1016/j.expneurol.2005.06.020Nagase H, 2005, BIOCHEM BIOPH RES CO, V337, P1330, DOI 10.1016/j.bbrc.2005.10.001Eun SY, 2006, EXP MOL MED, V38, P310Choi SY, 2007, BIOL PHARM BULL, V30, P772Nakajima A, 2007, J PHARMACOL EXP THER, V321, P784, DOI 10.1124/jpet.106.117010Choi SY, 2007, J ETHNOPHARMACOL, V113, P149, DOI 10.1016/j.jep.2007.05.021Nakajima A, 2007, J PHARMACOL SCI, V105, P122, DOI 10.1254/jphs.SC0070155CHRISTENSEN DZ, 2008, NEUROBIOL AGING, V31, P1153Ock J, 2009, PHARMACOL RES, V59, P414, DOI 10.1016/j.phrs.2009.02.008Lees AJ, 2009, LANCET, V373, P2055Yamamoto Y, 2009, BRAIN RES, V1295, P218, DOI 10.1016/j.brainres.2009.07.081Park GH, 2010, NITRIC OXIDE-BIOL CH, V22, P18, DOI 10.1016/j.niox.2009.10.008BOCCHINI V, 1992, J NEUROSCI RES, V31, P616BLASI E, 1990, J NEUROIMMUNOL, V27, P229