Biomedical subjects

Kerry R Delaney

Publications and source records attributed to Kerry R Delaney.

8 recordsLinked to original sources

PubMed2005

Brevity of the Ca2+ microdomain and active zone geometry prevent Ca2+-sensor saturation for neurotransmitter release.

The brief time course of the calcium (Ca2+) channel opening combined with the molecular-level colocalization of Ca2+ channels and synaptic vesicles in presynaptic terminals predict sub-millisecond calcium concentration ([Ca2+]) transients of > or = 100 microM in the immediate vicinity of the vesicle. This [Ca2+] is much higher than some of the recent estimates for the equilibrium dissociation constant of the Ca2+ sensor(s) that control neurotransmitter release, suggesting release should be close to saturation, yet it is well known that release is highly sensitive to changes in Ca2+ influx. We show that due to the brevity of the Ca2+ influx the binding kinetics of the Ca2+ sensor rather than its equilibrium affinity determine receptor occupancy. For physiologically relevant Ca2+ currents and forward Ca2+ binding rates, the effective affinity of the Ca2+ sensor can be several-fold lower than the equilibrium affinity. Using simple models, we show redundant copies of the binding sites increase effective affinity of the Ca2+ sensor for release. Our results predict that different levels of expression of Ca2+ binding sites could account for apparent differences in Ca2+ sensor affinities between synapses. Using Monte Carlo simulations of Ca2+ dynamics with nanometer resolution, we demonstrate that these kinetic constraints combined with vesicles acting as diffusion barriers can prevent saturation of the Ca2+-sensor(s) for neurotransmitter release. We further show the random positioning of the Ca2+-sensor molecules around the vesicle can result in the emergence of two distinct populations of the vesicles with low and high release probability. These considerations allow experimental evidence for the Ca2+ channel-vesicle colocalization to be reconciled with a high equilibrium affinity for the Ca2+ sensor of the release machinery.

Animals↗

PubMed2005

Interaction between facilitation and presynaptic inhibition at the crayfish neuromuscular junction.

Action potential-mediated calcium (Ca) entry into excitor nerve terminal boutons during presynaptic inhibition and the effects of co-activation of the inhibitor on the kinetics of muscle contraction were studied at crayfish claw opener muscle. Inhibition reduced postsynaptic excitatory junction potentials (EJPs) below the threshold to initiate contraction. Upon cessation of inhibition, EJP amplitudes immediately increased several-fold due to the build-up of presynaptic facilitation during inhibition. Consequently, muscle contraction was initiated more rapidly after a period of inhibitor-excitor coactivation. Presynaptic inhibition reduced Ca entry into presynaptic excitor terminal boutons (range 0-50%, mean +/-s.e.m.=20+/-1%, N=122 terminals; 12 preparations) and reduced the EJP amplitude (range 30-70%, mean +/- s.e.m.=51+/-2%, N=27 cells). The decline in the EJP was proportional to the reduction of Ca influx raised to the power of 2.8. Since presynaptic inhibition reduces the number of Ca channels opened by an action potential, our data suggest cooperativity between Ca channel microdomains to initiate vesicle fusion at this synapse. The amount of inhibition of Ca influx into an excitor bouton was not correlated with either the distance to the closest inhibitor bouton or the main excitor branch, although slightly more inhibition was seen for excitor boutons on tertiary versus secondary branches. Unlike inhibitor axon stimulation, bath application of GABA caused inhibition of Ca influx that steadily increased from proximal to distal terminal boutons on a branch. We propose a model where presynaptic inhibition causes localized shunting of an actively propagated action potential in the vicinity of release sites, which can recover its amplitude outside the shunted region.

Action Potentials↗

PubMed2004

Dopamine inhibits mitral/tufted--> granule cell synapses in the frog olfactory bulb.

Synaptic interactions between the dendrites of mitral/tufted (MT) and granule cells (GCs) in the olfactory bulb are important for the determination of spatiotemporal firing patterns of MTs, which form an odor representation passed to higher brain centers. These synapses are subject to modulation from several sources originating both within and outside the bulb. We show that dopamine, presumably released by TH-positive local interneurons, reduces synaptic transmission from MTs to GCs. MT neurons express D2-like receptors (D2Rs), and both dopamine and the D2 agonist quinpirole decrease EPSC amplitude at the MT--> GC synapse. D2R activation also increases paired pulse facilitation and decreases the frequency of action potential-independent spontaneous miniature EPSCs in GCs, consistent with an effect on MT glutamate release downstream from Ca2+ influx. Analysis of spike-evoked Ca2+ transients in MT lateral dendrites additionally shows that quinpirole reduces Ca2+ influx preferentially at distal locations, possibly by reducing dendritic excitability via increased transient K+ channel availability. When the OB is activated physiologically by using odor stimuli, blocking D2Rs increases the power of GABA(A)-dependent oscillations in the local field potential. This demonstrates a functional role for the dopaminergic circuit during normal odor-evoked responses and for the modulation of dendritic release and excitability in neuronal circuit function. Regulation of spike invasion of lateral dendrites by transient K+ currents also may provide a mechanism for local outputs of MTs to be controlled dynamically via other neuromodulators or by postsynaptic potentials.

4-Aminopyridine↗

PubMed2004

Competition between phasic and asynchronous release for recovered synaptic vesicles at developing hippocampal autaptic synapses.

Developing hippocampal neurons in microisland culture undergo rapid and extensive transmitter release-dependent depression of evoked (phasic) excitatory synaptic activity in response to 1 sec trains of 20 Hz stimulation. Although evoked phasic release was attenuated by repeated stimuli, asynchronous (miniature like) release continued at a high rate equivalent to approximately 2.8 readily releasable pools (RRPs) of quanta/sec. Asynchronous release reflected the recovery and immediate release of quanta because it was resistant to sucrose-induced depletion of the RRP. Asynchronous and phasic release appeared to compete for a common limited supply of release-ready quanta because agents that block asynchronous release, such as EGTA-AM, led to enhanced steady-state phasic release, whereas prolongation of the asynchronous release time course by LiCl delayed recovery of phasic release from depression. Modeling suggested that the resistance of asynchronous release to depression was associated with its ability to out-compete phasic release for recovered quanta attributable to its relatively low release rate (up to 0.04/msec per vesicle) stimulated by bulk intracellular Ca2+ concentration ([Ca2+]i) that could function over prolonged intervals between successive stimuli. Although phasic release was associated with a considerably higher peak rate of release (0.4/msec per vesicle), the [Ca2+]i microdomains that trigger it are brief (1 msec), and with asynchronous release present, relatively few quanta can accumulate within the RRP to be available for phasic release. We conclude that despite depression of phasic release during train stimulation, transmission can be maintained at a near-maximal rate by switching to an asynchronous mode that takes advantage of a bulk presynaptic [Ca2+]i.

Animals↗

PubMed2004

War-related psychological stressors and risk of psychological disorders in Australian veterans of the 1991 Gulf War.

BACKGROUND: Questions remain about the long-term health impacts of the 1991 Gulf War on its veterans. AIMS: To measure psychological disorders in Australian Gulf War veterans and a military comparison group and to explore any association with exposure to Gulf War-related psychological stressors. METHOD: Prevalences of DSM-IV psychological disorders were measured using the Composite International Diagnostic Interview. Gulf War-related psychological stressors were measured using a service experience questionnaire. RESULTS: A total of 31% of male Gulf War veterans and 21% of the comparison group met criteria for a DSM-IV disorder first present in the post-Gulf War period. The veterans were at greater risk of developing post-Gulf War anxiety disorders including post-traumatic stress disorder, affective disorders and substance use disorders. The prevalence of such disorders remained elevated a decade after deployment. The findings can be explained partly as a 'war-deployment effect'. There was a strong dose-response relationship between psychological disorders and number of reported Gulf War-related psychological stressors. CONCLUSIONS: Service in the 1991 Gulf War is associated with increased risk of psychological disorders and these are related to stressful experiences.

Adult↗

PubMed2004

Consequences of molecular-level Ca2+ channel and synaptic vesicle colocalization for the Ca2+ microdomain and neurotransmitter exocytosis: a monte carlo study.

Morphological and biochemical studies indicate association between voltage-gated Ca2+ channels and the vesicle docking complex at vertebrate presynaptic active zones, which constrain the separation between some Ca2+ channels and vesicles to 20 nm or less. To address the effect of the precise geometrical relationship among the vesicles, the Ca2+ channel, and the proteins of the release machinery on neurotransmitter release, we developed a Monte Carlo simulation of Ca2+ diffusion and buffering with nanometer resolution. We find that the presence of a vesicle as a diffusion barrier alters the shape of the Ca2+ microdomain of a single Ca2+ channel around the vesicle. This effect is maximal in the vicinity of the vesicle and depends critically on the vesicle's distance from the plasmalemma. Ca2+-sensor(s) for release would be exposed to markedly different [Ca2+], varying by up to 13-fold, depending on their position around the vesicle. As a result, the precise position of Ca2+-sensor(s) with respect to the vesicle and the channel can be critical to determining the release probability. Variation in the position of Ca2+-sensor molecule(s) and their accessibility could be an important source of heterogeneity in vesicle release probability.

Calcium↗

PubMed2002

Tyrosine hydroxylase-immunoreactive interneurons in the olfactory bulb of the frogs Rana pipiens and Xenopus laevis.

We studied tyrosine hydroxylase (TH)-immunoreactive neurons and neuropil in the olfactory bulb of the leopard frog, Rana pipiens, and in the clawed frog, Xenopus laevis. In both frogs, TH processes in the main olfactory bulb showed a trilaminar organization, with a densely stained external glomerular layer (GL), a moderately stained middle mitral cell layer (MCL), and internally a weakly stained internal plexiform layer (IPL) and granule cell layer (GRL). TH-positive cells in the MCL and IPL could be divided into two types. Type 1 cells had one or two thick dendrites that arborized within glomeruli in the GL and often had a thin "axon-like" process that exited the cell on the internal surface, with a recurrent collateral that ascended into the GL. Type 2 cells had beaded dendrites arborizing in the MCL and no discernible axons. Both type 1 and type 2 cells were numerous in the MCL and IPL of Rana, whereas only type 2 cells were common in the MCL and IPL of Xenopus. In the GL, labeled cells were numerous in Xenopus but rare in Rana. Mitral cells were stained retrogradely by tracer injection into the lateral olfactory tract and by local injection into the bulb. In no case was double labeling for TH observed, suggesting that TH-positive cells in frog olfactory bulb are likely to be interneurons. Double labeling with an anti-gamma-aminobutyric acid (GABA) antibody showed that the TH-positive cells formed a population separate from the GABA-containing interneurons.

Animals↗

PubMed2002

Contribution of a calcium-activated non-specific conductance to NMDA receptor-mediated synaptic potentials in granule cells of the frog olfactory bulb.

We studied granule cells (GCs) in the intact frog olfactory bulb (OB) by combining whole-cell recordings and functional two-photon Ca(2+) imaging in an in vitro nose-brain preparation. GCs are local interneurones that shape OB output via distributed dendrodendritic inhibition of OB projection neurones, the mitral-tufted cells (MTCs). In contrast to MTCs, GCs exhibited a Ca(2+)-activated non-specific cation conductance (I(CAN)) that could be evoked through strong synaptic stimulation or suprathreshold current injection. Photolysis of the caged Ca(2+) chelator o-nitrophenol-EGTA resulted in activation of an inward current with a reversal potential within the range -20 to +10 mV. I(CAN) in GCs was suppressed by the intracellular Ca(2+) chelator BAPTA (0.5-5.0 mM), but not by EGTA (up to 5 mM). The current persisted in whole-cell recordings for up to 1.5 h post-breakthrough, was observed during perforated-patch recordings and was independent of ionotropic glutamate and GABA(A) receptor activity. In current-clamp mode, GC responses to synaptic stimulation consisted of an initial AMPA-mediated conductance followed by a late-phase APV-sensitive plateau (100-500 ms). BAPTA-mediated suppression of I(CAN) resulted in a selective reduction of the late component of the evoked synaptic potential, consistent with a positive feedback relationship between NMDA receptor (NMDAR) current and I(CAN). I(CAN) requires Ca(2+) influx either through voltage-gated Ca(2+) channels or possibly NMDARs, both of which have a high threshold for activation in GCs, predicting a functional role for this current in the selective enhancement of strong synaptic inputs to GCs.

2-Amino-5-phosphonovalerate↗