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Medical Sciences	75%

Selected Abstracts

Presynaptic source of quantal size variability at GABAergic synapses in rat hippocampal neurons in culture

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2004
Andrea Barberis
Abstract The variability of quantal size depends on both presynaptic (profile of the neurotransmitter concentration in the cleft) and postsynaptic (number and gating properties of postsynaptic receptors) factors. Here we have examined the possibility that at nonsaturated synapses in cultured hippocampal neurons, changes in both the transmitter concentration peak and its clearance from the synaptic cleft may influence the variability of spontaneous miniature synaptic GABAergic currents (mIPSCs). We found that, in contrast to the slow-off GABAA receptor antagonist bicuculline, fast-off competitive antagonists such as SR-95103 and TPMPA differentially blocked small and large mIPSCs. In the presence of flurazepam, a drug believed to increase the affinity of GABA for GABAAR, small mIPSCs were enhanced more efficiently than large events. Moreover, the addition of dextran, which increases the viscosity of the extracellular fluid, preferentially increased small mIPSCs with respect to large ones. These observations suggest that changes in the concentration peak and the speed of GABA clearance in the cleft may be an important source of synaptic variability. The study of the correlation between peak amplitude and kinetics of mIPSCs allowed determination of the relative contribution of transmitter peak concentration vs. time of GABA clearance. Small synaptic responses were associated with fast onset and decay kinetics while large amplitude currents were asociated with slow kinetics, indicating a crucial role for GABA synaptic clearance in variability of mIPSCs. By using model simulations we were able to estimate the range of variability of both the concentration and the speed of clearance of the GABA transient in the synaptic cleft. [source]

Orthodontically stressed periodontium of transgenic mouse as a model for studying mechanical response in bone: The effect on the number of osteoblasts

ORTHODONTICS & CRANIOFACIAL RESEARCH, Issue 2 2000
Dubravko Pavlin
A better understanding of cellular and molecular mechanisms involved in response to mechanical stress is a prerequisite for future improvements in orthodontic treatment. To expand the application of molecular biology techniques in this area of research, we developed and characterized a mouse tooth movement model. The aim of this study was to biomechanically characterize this model and to evaluate the effect of orthodontic stress on the proliferation of periodontal osteoblasts. We used an orthodontic coil spring appliance with a low force/deflection rate, which produced an average force of 10,12 g. This design provided a predictable tipping movement of the molar with the center of rotation at the level of root apices. Histological observations of paradental tissues revealed a response favoring a fast onset of tooth movement and deposition of new osteoid starting after 3 days of treatment. The effect of treatment on the histomorpometric parameter of the number of osteoclasts per unit bone perimeter was determined after 1, 2, 3, 4, 6, and 12 days of treatment. Starting with day 2, the osteoblast number showed a modest but consistent increase in treated periodontal sites at all time-points, ranging from 14 to 39% and becoming significant only at day 6. Only a moderate increase in the number of osteoblasts in the areas of otherwise intense bone matrix synthesis suggests that, during bone formation, proliferation of cells has a smaller role compared to a marked increase in differentiation of individual cells. The mouse model, which allows for a controlled, reproducible, orthodontic mechanical loading, can be applied to both wild-type and transgenic animals and should enhance the research of the transduction of mechanical orthodontic signal into a biological response. [source]

Studies on the mechanisms of action of picrotoxin, quercetin and pregnanolone at the GABA,1 receptor

BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2004
Juan D Goutman
The mechanisms of action of antagonists of the , -aminobutyric acid C (GABAC) receptor picrotoxin, quercetin and pregnanolone were studied. Ionic currents (chloride), mediated through human homomeric GABA,1 receptors expressed in Xenopus oocytes, were recorded by two-electrode voltage clamp. Dose,response (D,R) curves and kinetic measurements of GABA,1 currents were carried out in the presence or absence of antagonists. Use-dependent actions were also evaluated. Picrotoxin, quercetin and pregnanolone exerted noncompetitive actions. IC50 values measured at the EC50 for GABA (1 ,M) were as follows: picrotoxin 0.6±0.1 ,M (Hill coefficient n=1.0±0.2); quercetin 4.4±0.4 ,M (n=1.5±0.2); pregnanolone 2.1±0.5 ,M (n=0.8±0.1). These antagonists produced changes only in the slope of the linear current,voltage relationships, which was indicative of voltage-independent effects. The effect of picrotoxin on GABA,1 currents was use-dependent, strongly relied on agonist concentration and showed a slow onset and offset. The mechanism was compatible with an allosteric inhibition and receptor activation was a prerequisite for antagonism. The effect of quercetin was use-independent, showed relatively fast onset and offset, and resulted in a slowed time course of the GABA-evoked currents. The effect of pregnanolone was use-independent, presented fast onset and a very slow washout, and did not affect current activation. All the antagonists accelerated the time course of deactivation of the GABA,1 currents. British Journal of Pharmacology (2004) 141, 717,727. doi:10.1038/sj.bjp.0705657 [source]