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PubMed1987

The actions of THC on the intact hippocampus: a comparison of dentate and CA1 responses.

The effects of delta-9-tetrahydrocannabinol were compared on two afferent pathways of the rat hippocampal formation in urethane-anesthetized and chronically implanted awake animals. In urethane-anesthetized rats, THC produced a shift to the right in the input/output relationship without altering the relation between the measures of synaptic wave and the population spike of the CA1 response to contralateral CA3 stimulation. In contrast, the dentate response to perforant path stimulation was not altered by THC. Awake rats exhibited a similar response to THC, however, the CA1 response was less sensitive to THC and there was no change in the maximal response as there was in the anesthetized rat. Paired pulse studies demonstrated that there was a significant increase in paired pulse inhibition at 8 mg/kg in the CA1 region. There was no significant alteration of the dentate response to perforant path stimulation in the awake rat. These results suggest that alterations in limbic electrophysiology induced by THC may be mediated by structures other than the hippocampus.

Animals↗
PubMed1999

Signal pathway of mitogen-induced Ca2+-activated K+ currents in young and aged T-cell clones of C57BL/6 mice.

Signal transduction pathways of mitogenic plant lectin, concanavalin A (Con A)- and ionomycin (INM)-induced (Ca2+-dependent K+ currents (I(Con A) and I(INM)) have been compared in young and aged T-cell clones by using the nystatin perforated patch-clamp whole-cell recording technique. In young T-cell clones, Con A evoked a long-lasting outward current which is mediated by the activation of the Ca2+-dependent K+ channels. The Ca2+ ionophore, INM, evoked a short-lasting Ca2+-dependent outward K+ current (I(INM)). The protein tyrosine kinase (PTK) inhibitor, herbimycin A (3 x 10(-6) M), but not the G protein blocker, pertussis toxin (PTX, 500 ng ml(-1)), completely prevented the I(Con A), but did not affect the I(INM). In aged T-cell clones, Con A fails to evoke any current response, while INM evokes an outward current which is comparable to that in a young T-cell clone. It is concluded that PTK, but not PTX-sensitive G proteins, plays a critical role in mediation of the signal transduction from Con A stimulation to activation of the Ca2+-dependent K+ channels, and that an impairment of the early signal pathway, perhaps the PTK, might be involved in the mechanism of the age-related decline of the proliferative response of T-lymphocytes to mitogenic stimulation.

Animals↗
PubMed2000

Optical imaging reveals characteristic seizure onsets, spread patterns, and propagation velocities in hippocampal-entorhinal cortex slices of juvenile rats.

We have combined recordings with extracellular microelectrodes or ion-sensitive electrodes and imaging of intrinsic optical signal changes to study the spatiotemporal pattern of seizure onset and spread during development. We have employed the entorhinal cortex-hippocampus brain slice preparation of juvenile rats at different stages of postnatal maturation. Three age groups were analyzed: 4-6 days (age group I), 10-14 days (age group II), and 20-23 days (age group III). Seizure-like events were induced by perfusion of slices with Mg(2+)-free artificial cerebrospinal fluid thereby removing the Mg(2+) block of the N-methyl-d-aspartate receptor. Seizure susceptibility was highest in age groups II and III. In age group I seizure-like events originated mainly in the hippocampus proper. Seizure-like events in age group II originated mainly in the entorhinal cortex and this tendency was even more pronounced in age group III. Invasion of the hippocampal formation via the perforant path-dentate gyrus and via the subiculum was seen in age groups I and II. In contrast, in age group III the hippocampus was invaded exclusively via the subiculum pathway. The velocity of spread at which seizure-like events propagated within different regions of the slice increased with postnatal age. The characteristics of onset, spread patterns, and propagation velocities as revealed by this study allow insight into the evolving properties of the developing brain.

Action Potentials↗
PubMed2006

Katanin disrupts the microtubule lattice and increases polymer number in C. elegans meiosis.

Katanin is a heterodimer that exhibits ATP-dependent microtubule-severing activity in vitro. In Xenopus egg extracts, katanin activity correlates with the addition of cyclin B/cdc2, suggesting a role for microtubule severing in the disassembly of long interphase microtubules as the cell prepares for mitosis. However, studies from plant cells, cultured neurons, and nematode embryos suggest that katanin could be required for the organization or postnucleation processing of microtubules, rather than the dissolution of microtubule structures. Here we reexamine katanin's role by studying acentrosomal female meiotic spindles in C. elegans embryos. In mutant embryos lacking katanin, microtubules form around meiotic chromatin but do not organize into bipolar spindles. By using electron tomography, we found that katanin converts long microtubule polymers into shorter microtubule fragments near meiotic chromatin. We further show that turning on katanin during mitosis also creates a large pool of short microtubules near the centrosome. Furthermore, the identification of katanin-dependent microtubule lattice defects supports a mechanism involving an initial perforation of the protofilament wall. Taken together, our data suggest that katanin is used during meiotic spindle assembly to increase polymer number from a relatively inefficient chromatin-based microtubule nucleation pathway.

Adenosine Triphosphatases↗
PubMed1997

Parvalbumin disappears from GABAergic CA1 neurons of the gerbil hippocampus with seizure onset while its presence persists in the perforant path.

Mongolian gerbils are epilepsy prone animals, a trait observable at the behavioural level during the 2nd month of life. As a unique species difference, gerbils express the calcium-binding protein parvalbumin (PV) in the perforant path from the entorhinal cortex to the hippocampus. In this study, we determined the time of appearance of PV in the layer II neurons of the entorhinal cortex and the perforant path terminals in gerbils between post-natal days 30 and 50. Signs of low grade seizures were observed in few animals from P40 onward. PV stain in the entorhinal cortex and perforant path terminals was already detectable at P30, well before the onset of behavioural seizures and did not change with age. It is suggested that the presence of PV in this pathway may be related to the generation early in life of an epileptogenic focus in the limbic forebrain. Altered inhibitory hippocampal circuits have also been suggested as a cause of seizures in the gerbil. Therefore, we quantitated hippocampal GABA-immunoreactive neurons and the PV-immunoreactive subpopulation. A group of gerbils with a high density of stained pyramidal interneurons in CA1 and one lacking PV-stained perikarya could be distinguished at P40 and P50. The density of GABA-immunoreactive nerve cells however, remained the same in both groups and through the ages studied. Thus, perikaryal PV is lost from intact GABAergic nerve cells at the same time as behavioural seizures are observed. The loss of PV from GABAergic neurons may affect their functional properties and be instrumental for the maintainance of behavioural seizures.

Age of Onset↗
PubMed1976

[Formation of cellular structures and interneuronal connections in an organotypic culture of newborn mouse hippocampal tissue].

The cytoarchitectonic structures and fibres pathways of the newborn mouse hippocampus were studied in vitro. After 2-3 weeks in vitro it was possible to see on transverse slices of the hippocampus main fascicles (alvear tract, perforant path, axons of granular cells) and cytoarchitectonic formations (pyramidal cell layer of hippocampus, infra- and supra-pyramidal lymbs of dentate gyrus granular cells). The postnatal processes of histogenesis are suggested to result in subsequent differentiation of the cytoarchitectonic formations and in the systemic growth of nerve fibres in the hippocampus explants. Thus, organo-typic explants of the hippocampus represent a useful model systems for electrophysiological studies in systemic interneuronal connections formed de novo as a result of postnatal development in vitro.

Animals↗
PubMed1989

Buttock abscess complicating Crohn's disease.

Two patients with buttock abscesses developing as an extension of Crohn's disease are described. In each, the abscess extended through the sciatic foramen into gluteal soft tissues. Cross-sectional imaging, particularly computed tomography, is of major help in identifying these lesions and the pathway of spread.

Abscess↗
PubMed2004

Gramicidin-perforated patch recording revealed the oscillatory nature of secretory Cl- movements in salivary acinar cells.

Elevations of cytoplasmic free calcium concentrations ([Ca(2+)](i)) evoked by cholinergic agonists stimulate isotonic fluid secretion in salivary acinar cells. This process is driven by the apical exit of Cl(-) through Ca(2+)-activated Cl(-) channels, while Cl(-) enters the cytoplasm against its electrochemical gradient via a loop diuretic-sensitive Na(+)-K(+)-2Cl(-) cotransporter (NKCC) and/or parallel operations of Cl(-)-HCO(3)(-) and Na(+)-H(+) exchangers, located in the basolateral membrane. To characterize the contributions of those activities to net Cl(-) secretion, we analyzed carbachol (CCh)-activated Cl(-) currents in submandibular acinar cells using the "gramicidin-perforated patch recording configuration." Since the linear polypeptide antibiotic gramicidin creates monovalent cation-selective pores, CCh-activated Cl(-) currents in the gramicidin-perforated patch recording were carried by Cl(-) efflux via Cl(-) channels, dependent upon Cl(-) entry through Cl(-) transporters expressed in the acinar cells. CCh-evoked oscillatory Cl(-) currents were associated with oscillations of membrane potential. Bumetanide, a loop diuretic, decreased the CCh-activated Cl(-) currents and hyperpolarized the membrane potential. In contrast, neither methazolamide, a carbonic anhydrase inhibitor, nor elimination of external HCO(3)(-) had significant effects, suggesting that the cotransporter rather than parallel operations of Cl(-)-HCO(3)(-) and Na(+)-H(+) exchangers is the primary Cl(-) uptake pathway. Pharmacological manipulation of the activities of the Ca(2+)-activated Cl(-) channel and the NKCC revealed that the NKCC plays a substantial role in determining the amplitude of oscillatory Cl(-) currents, while adjusting to the rate imposed by the Ca(2+)-activated Cl(-) channel, in the gramicidin-perforated patch configuration. By concerting with and being controlled by the cation steps, the oscillatory form of secretory Cl(-) movements may effectively provide a driving force for fluid secretion in intact acinar cells.

Angiogenesis Inhibitors↗
PubMed1998

Stimulation of NTS activates NMDA and non-NMDA receptors in rat cardiac vagal neurons in the nucleus ambiguus.

While it is widely accepted that tonic and reflex changes in cardiac vagal activity play significant roles in cardiovascular function, little is known about the synaptic pathways in the brainstem responsible for the control of cardiac vagal neurons in the nucleus ambiguus (NA). In this study, we identified the principal post-synaptic receptors activated in cardiac vagal neurons upon stimulation of the nucleus tractus solitarius (NTS). Cardiac vagal neurons were identified by the presence of a retrograde fluorescent tracer and were visualized in rat brainstem slices. Perforated patch clamp techniques were used to record post-synaptic currents. NTS stimulation activated glutamatergic currents in cardiac vagal neurons with a typical delay of 8-18 ms. Post-synaptic responses were separated into NMDA and non-NMDA components using D-2-amino-5-phophonovalerate (AP5) and 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX), respectively. In conclusion, this study characterizes a monosynaptic glutamatergic pathway from NTS that activates NMDA and kainate/AMPA post-synaptic receptors in cardiac vagal neurons.

2-Amino-5-phosphonovalerate↗
PubMed1997

cAMP increases apical IsK channel current and K+ secretion in vestibular dark cells.

Adenosine 3',5'-cyclic monophosphate (cAMP) is known to stimulate exogenous IsK channel current in the Xenopus oocyte expression system. The present study was performed to determine whether elevation of cytosolic cAMP in a native mammalian epithelium known to secrete K+ through endogenously expressed IsK channels would stimulate K+ secretion through these channels. The equivalent short circuit current (Isc) across vestibular dark cell epithelium in gerbil was measured in a micro-Ussing chamber and the apical membrane current (IsK) and conductance (gIsK) of IsK channels was recorded with both the on-cell macro-patch and nystatin-perforated whole-cell patch-clamp techniques. It has previously been shown that Isc can be accounted for by transepithelial K+ secretion and that the apical IsK channels constitute a significant pathway for K+ secretion. The identification of the voltage-dependent whole-cell currents in vestibular dark cells was strengthened by the finding that a potent blocker of IsK channels, chromanol 293B, strongly reduced IIsK from 646 +/- 200 to 154 +/- 22 pA (71%) and gIsK from 7.5 +/- 2.6 to 2.8 +/- 0.4 nS (53%). Cytoplasmic cAMP was elevated by applying dibutyryl cyclic AMP (dbcAMP), or the phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX) and Ro-20-1724. dbcAMP (1 mM) increased Isc and IIsK from 410 +/- 38 to 534 +/- 40 microA/cm2 and from 4.3 +/- 0.8 to 11.4 +/- 2.2 pA, respectively. IBMX (1 mM) caused transient increases of Isc from 415 +/- 30 to 469 +/- 38 microA/cm2 and Ro-20-1724 (0.1 mM) from 565 +/- 43 to 773 +/- 58 microA/cm2. IBMX increased IIsK from 5.5 +/- 1.5 to 16.9 +/- 5.8 pA in on-cell experiments and from 191 +/- 31 to 426 +/- 53 pA in whole-cell experiments. The leak conductance due to all non-IsK channel sources did not change during dbcAMP and IBMX while 293B in the presence of dbcAMP reduced IIsK by 84% and gIsK by 62%, similar to unstimulated conditions. These results demonstrate that the cAMP pathway is constitutively active in vestibular dark cells and that the cAMP pathway stimulates transepithelial K+ secretion by increasing IsK channel current rather than by altering another transport pathway.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Chronic epileptogenesis induced by kindling of the entorhinal cortex: the role of the dentate gyrus.

The role of the dentate gyrus (DG) in the development and maintenance of kindling induced by periodic electrical stimulation of the entorhinal cortex (EC) was evaluated in rats. Colchicine, a selective neurotoxin for granule cells of the DG, was injected into the DG: prior to kindling and after the development of kindling. Prior destruction of the DG delayed the development of afterdischarge (AD) induced by EC stimulation, but kindling proceeded at normal rates after the first AD was induced. Destruction of the DG after kindling did not abolish the kindled seizures. Thus, the DG was not required for either the development or maintenance of kindling by EC stimulation, but an intact perforant path input from the EC to DG facilitated the emergence of epileptogenesis by kindling of the EC. The results suggest that kindling develops and is maintained in a network of multiple pathways which are related to the site of stimulation. The DG appears to be the site of a temporally specific alteration which facilitates the development of kindling by EC stimulation.

Animals↗
PubMed2001

Molecular mechanisms contributing to necrotizing enterocolitis.

OBJECTIVE: To examine the cellular mechanisms involved in the pathogenesis of necrotizing enterocolitis (NEC). SUMMARY BACKGROUND DATA: Necrotizing enterocolitis is a major cause of death and complications in neonates; the cellular mechanisms responsible for NEC are unknown. The inducible form of cyclooxygenase (i.e., COX-2) is activated by the transcription factor nuclear factor (NF)-kappaB and is thought to play a role in inflammation. METHODS: Segments of perforated and adjacent uninvolved small intestine from neonates with NEC were analyzed for COX-2 expression by immunohistochemistry. NEC was induced in weanling (18 days old) rats by occlusion of superior mesenteric vessels for 1 hour and intraluminal injection of platelet activating factor (50 micro/kg). Small intestine was harvested for protein extraction. Western immunoblot was performed to determine expression of COX-2. Gel shift assays were performed to assess NF-kappaB binding activity. RESULTS: Immunohistochemical analysis showed increased COX-2 protein expression in the perforated intestinal sections of all 36 neonates but not in adjacent normal intestine. Increased expression of COX-2 protein and NF-kappaB binding activity was noted in the small intestine of weanling rats at 0 and 3 hours after induction of NEC. CONCLUSIONS: Increased COX-2 expression was identified in all neonatal intestinal segments resected for perforated NEC. In addition, a coordinate induction of COX-2 expression and NF-kappaB binding was noted in a rodent model of NEC. These findings suggest that the COX-2/NF-kappaB pathway may play a role in the pathogenesis of NEC. Therapeutic agents that target this pathway may prove useful in the treatment or possible prevention of NEC.

Animals↗
PubMed2003

Opposite action of beta1- and beta2-adrenergic receptors on Ca(V)1 L-channel current in rat adrenal chromaffin cells.

Voltage-gated Ca(2+) channels of chromaffin cells are modulated by locally released neurotransmitters through autoreceptor-activated G-proteins. Clear evidence exists in favor of a Ca(2+) channel gating inhibition mediated by purinergic, opioidergic, and alpha-adrenergic autoreceptors. Few and contradictory data suggest also a role of beta-adrenergic autoreceptors (beta-ARs), the action of which, however, remains obscure. Here, using patch-perforated recordings, we show that rat chromaffin cells respond to the beta-AR agonist isoprenaline (ISO) by either upmodulating or downmodulating the amplitude of Ca(2+) currents through two distinct modulatory pathways. ISO (1 microm) could cause either fast inhibition (approximately 25%) or slow potentiation (approximately 25%), or a combination of the two actions. Both effects were completely prevented by propranolol. Slow potentiation was more evident in cells pretreated with pertussis toxin (PTX) or when beta(1)-ARs were selectively stimulated with ISO + ICI118,551. Potentiation was absent when the beta(2)-AR-selective agonist zinterol (1 microm), the protein kinase A (PKA) inhibitor H89, or nifedipine was applied, suggesting that potentiation is associated with a PKA-mediated phosphorylation of L-channels (approximately 40% L-current increase) through beta(1)-ARs. The ISO-induced inhibition was fast and reversible, preserved in cell treated with H89, and mimicked by zinterol. The action of zinterol was mostly on L-channels (38% inhibition). Zinterol action preserved the channel activation kinetics, the voltage-dependence of the I-V characteristic, and was removed by PTX, suggesting that beta(2)AR-mediated channel inhibition was mainly voltage independent and coupled to G(i)/G(o)-proteins. Sequential application of zinterol and ISO mimicked the dual action (inhibition/potentiation) of ISO alone. The two kinetically and pharmacologically distinct beta-ARs signaling uncover alternative pathways, which may serve the autocrine control of Ca(2+)-dependent exocytosis and other related functions of rat chromaffin cells.

Adrenal Glands↗
PubMed2004

Involvement of TRPM7 in cell growth as a spontaneously activated Ca2+ entry pathway in human retinoblastoma cells.

We investigated the possible involvement of the melastatin family protein TRPM7 in Ca(2+)-mediated proliferative control of human retinoblastoma (RB) cells. The growth of RB cell was facilitated by elevating the extracellular Ca(2+) concentration with a parallel increase in the magnitude of spontaneous Ca(2+) influx. Under nystatin-perforated voltage-clamp, RB cells exhibited an outward-rectifying, spontaneous cation current (I(spont)) having Ca(2+)/Mg(2+)-inhibited but -permeating properties. Various cation channel blockers inhibiting I(spont) (Gd(3+), La(3+), LOE908, 2-APB) suppressed the spontaneous Ca(2+) influx and decelerated the growth of RB cells with similar efficacies. Excision of the RB cell membrane (inside-out) into MgATP-free solution induced a 70pS single channel activity, which was effectively inhibited by millimolar concentrations of Mg(2+) or MgATP. RT-PCR and immunocytochemical experiments revealed the expression of TRPM7 mRNA and protein in RB cells, and heterologous expression of TRPM7 in HEK293 cells reproduced the key features of I(spont). In contrast, elimination of this protein from RB cells by siRNA silencing markedly reduced I(spont) density and the magnitude of spontaneous Ca(2+) influx, which was paralleled by decreased TRPM7 immunoreactivity, decelerated cell proliferation, and retarded G(1)/S cell cycle progression. These results suggest a significant regulatory role of TRPM7 for RB cell proliferation as a spontaneously activated Ca(2+) influx pathway.

Calcium↗
PubMed2002

Odontogenic infection pathway to the submandibular space: imaging assessment.

The aims of this study were to determine the pathways of odontogenic infection spread into the submandibular space and their relationship to the clinical symptoms. Computerized tomography (CT) and magnetic resonance (MR) images of 33 patients with submandibular involvement were analyzed. The spread of infection was evaluated by lateral asymmetry of the shape and density of the fascial spaces and tissues, and by obliteration of the interfascial fat spaces. Imaging findings were classified into three types: in 19 patients (57.6%), infection spread through the mylohyoid muscle or sublingual space (type I). In five patients (15.2%), infection spread through the bony structures of the mandible with periosteal reaction or perforation of the cortical plate (type II) and was associated with relatively mild symptoms. In four patients (12.1%), infection spread from the masticatory space (type III). Seven of 11 patients with dysphagia or fever showed submandibular involvement spreading into the parapharyngeal space. CT and MR imaging clearly demonstrated different pathways of the spread of odontogenic infection into the submandibular space, which influenced the manifestation of clinical symptoms.

Adipose Tissue↗
PubMed2000

Endothelium-dependent relaxation in perforating branch of human internal mammary artery.

The purpose of the present study was to examine the effect of acetylcholine on perforating branch of the human internal mammary artery (HIMA). Acetylcholine (10(-9)-10(-5)M) induced concentration- and endothelium-dependent relaxation (pEC(50)=7.54+/-0.03, maximal response was 98+/-1.3%) of the precontracted arterial segments. Indomethacin, 4-aminopyridine (10(-5)M) and precontraction with K(+)-rich Krebs-Ringer-bicarbonate solution had no effect on acethylcholine-induced relaxation. N(G)-monomethyl-L-arginine (L-NMMA) (10(-5)M) inhibited relaxation evoked by acetylcholine. Indomethacin applied together with L-NMMA lead to further inhibition of acethylcholine-induced relaxation. Even in the presence of both L-NMMA and indomethacin, 4-aminopyridine had no provoked further inhibition of acetylcholine-induced relaxation of perforating branch of HIMA. It was concluded that the acethylcholine-induced relaxation of isolated perforating branch of HIMA is probably mediated via endothelial production of nitric oxide. However, when NO-synthase is inhibited, acetylcholine-induced vasorelaxation may be, in part, mediated through activation of cyclooxygenase pathway and consequent production and release of prostacyclin or some other cyclooxygenase products.

Acetylcholine↗
PubMed1996

Progressive entorhinal cortex lesions accelerate hippocampal sprouting and spare spatial memory in rats.

Accelerating hippocampal sprouting by making unilateral progressive lesions of the entorhinal cortex spared the spatial memory of rats tested for retention of a learned alternation task. Subsequent transection of the sprouted crossed temporodentate pathway (CTD), as well as a simultaneous CTD transection and progressive entorhinal lesion, produced a persistent deficit on the memory task. These results suggest that CTD sprouting, which is homologous to the original perforant path input to the dentate gyrus of the hippocampus, is behaviorally significant and can ameliorate at least some of the memory deficits associated with hippocampal deafferentation.

Animals↗