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Biomedical subjects

R L Cooper

Publications and source records attributed to R L Cooper.

At least 73 records · Page 4Linked to original sources
PubMed1998

Depression of synaptic efficacy at intermolt in crayfish neuromuscular junctions by 20-hydroxyecdysone, a molting hormone.

This report demonstrates that ecdysteroids can reduce synaptic transmission at an intermolt stage of a crustacean tonic neuromuscular junction by acting at a presynaptic site. The steroid molting hormone, 20-hydroxyecdysone (20-HE), appears to act through a rapid, nongenomic mechanism that decreases the probability of synaptic vesicle release and reduces the number of release sites. Quantal analysis revealed that fewer vesicles were released for a given stimulus when 20-HE was present, and this in turn accounted for the reduced synaptic efficacy. Reduced synaptic efficacy produced smaller evoked postsynaptic currents and smaller excitatory postsynaptic potentials (EPSPs) across the muscle fiber membrane. The reduction in EPSPs was observed among muscle fibers that were innervated by high- or low-output terminals. The behavior of crustaceans/crayfish during the molt cycle, when 20-HE is high, may be explained by the reduction in synaptic transmission. Crustaceans become quiescent during the premolt periods as do insects. The effects of 20-HE can be reversed with the application of the crustacean neuromodulator serotonin, which enhances synaptic transmission.

Animals↗
PubMed1998

Development of sensory processes during limb regeneration in adult crayfish.

The capacity of the crayfish Procambarus clarkii to regenerate its walking legs provides a system for studying the mechanisms of neural regeneration and repair. A set number of excitatory and inhibitory motor neurons innervate all the limb musculature throughout the normal development and regeneration of a limb. The cell bodies of the motor neurons reside within the segmental ganglion and, upon loss of the limb, their axons regrow from their severed distal ends. The cell bodies of the sensory neurons, in contrast, are located close to their sensory endings within the limb, and they are therefore lost, along with the limb, upon autotomy, leaving the severed, distal axonal stumps of the sensory neurons within the ganglionic root. During the regeneration of a limb, new sensory neurons develop within the limb, and their axons must then grow into the ganglionic root to make the appropriate connections for the new limb to become functional. Evidence is presented in the present paper that the sensory axonal stumps do not degenerate before the new sensory neurons appear within the root as the limb regenerates. These results also indicate a progressive advance of growth cones, presumably sensory in origin, towards the neuropil within the ganglion over time.

Animals↗
PubMed1998

Environmental endocrine disruption: an effects assessment and analysis.

This report is an overview of the current state of the science relative to environmental endocrine disruption in humans, laboratory testing, and wildlife species. Background information is presented on the field of endocrinology, the nature of hormones, and potential sites for endocrine disruption, with specific examples of chemicals affecting these sites. An attempt is made to present objectively the issue of endocrine disruption, consider working hypotheses, offer opposing viewpoints, analyze the available information, and provide a reasonable assessment of the problem. Emphasis is placed on disruption of central nervous system--pituitary integration of hormonal and sexual behavioral activity, female and male reproductive system development and function, and thyroid function. In addition, the potential role of environmental endocrine disruption in the induction of breast, testicular, and prostate cancers, as well as endometriosis, is evaluated. The interrelationship of the endocrine and immune system is documented. With respect to endocrine-related ecological effects, specific case examples from the peer-reviewed literature of marine invertebrates and representatives of the five classes of vertebrates are presented and discussed. The report identifies some data gaps in our understanding of the environmental endocrine disruption issue and recommends a few research needs. Finally, the report states the U.S. Environmental Protection Agency Science Policy Council's interim position on endocrine disruption and lists some of the ongoing activities to deal with this matter.

Animals↗
PubMed1998

The correlation between cerebrospinal fluid pressure and retrolaminar tissue pressure.

PURPOSE: To measure the effects of cerebrospinal fluid pressure (CSFp) on retrolaminar tissue pressure (RLTp) and the translaminar pressure gradient (TLPG), particularly at low CSFp, which is the normal situation in erect posture. METHODS: Micropipettes coupled to a servonull pressure system were passed into eyes of anesthetized dogs to the optic disc and advanced in steps through the lamina cribrosa to the optic nerve subarachnoid space (ONSAS), while pressure measurements were taken. Cerebrospinal fluid pressure and intraocular pressure (IOP) were monitored and controlled. The TLPG was measured at varying IOPs and CSFps. The RLTp and ONSAS pressure (ONSASp) were measured at varying CSFps. In separate experiments, the optic nerve dura was incised, and pressure measurements were taken across the pia mater. RESULTS: The TLPG was strongly correlated to the difference between IOP and CSFp (r=0.93; n=18) when CSFp was more than zero. Mean RLTp was 3.7+/-0.2 mm Hg (SEM; n=15) when CSFp was 0 mm Hg. The ONSASp and RLTp were largely dependent on the presence of CSFp higher than break point pressures of -0.5 mm Hg and 1.33 mm Hg, respectively. However, below these break points, RLTp (slope 0.07) and ONSASp (slope 0.18) were little influenced by CSFp. Separate measurements across the pia mater revealed that 95% of the pressure drop occurred within 100 microm of the pial surface. CONCLUSIONS: The TLPG and RLTp are dependent on CSFp when CSFp is more than -0.5 mm Hg. Below this level, there is no hydrostatic continuity between the intracranial and optic nerve subarachnoid space. In this range, RLTp is stable and is little influenced by CSFp changes.

Animals↗
PubMed1997

Persistence of autoantibodies against recombinant mitochondrial and nuclear pore proteins after orthotopic liver transplantation for primary biliary cirrhosis.

Primary biliary cirrhosis is an autoimmune disease characterized by high titer autoantibodies predominantly against mitochondrial antigens PDC-E2, BCOADC-E2 and OGDC-E2. Currently orthotopic liver transplant (OLT) is the major form of treatment for end-stage primary biliary cirrhosis (PBC), but it is still unclear whether the autoimmune response continues post-transplantation. In this study we took advantage of a well-defined collection of sera collected serially before and after liver transplantation. We assayed these sera for quantitative and isotype-specific titers of antibodies against a set of recombinant mitochondrial autoantigens. We also studied reactivity to gp210. Serum samples were taken before transplantation and at intervals of 6 months, 1, 2, and 3 years after OLT. Before OLT 24/35 patients were AMA-positive, including seven out of the 35 to PDC-E2 alone, eight to both PDC-E2 and OGDC-E2, six to both PDC-E2 and BCOADC-E2, two to BCOADC-E2 alone and one to OGDC-E2. Following OLT, the frequency of sera that responded to PDC-E2 alone increased from seven to 12/35. Similarly, reactivity to BCOADC-E2 slightly increased from two to four out of 35. However, there was an overall decrease in sera that responded to more than one antigen. Neither Ig isotype nor subclass of the autoimmune response changed following OLT. Findings with gp210 were similar, in that reactivity to gp210 was found in nine out of 35 patients pre-OLT; following OLT the frequency decreased to seven out of 35 patients. Overall, the titers of AMAs decline slightly during the first year post-OLT, but are equivalent to pre-OLT values by 6 months. Moreover, the antibody subclass/ isotype remained unchanged. These data suggest that the removal of a diseased PBC liver has little, if any, impact on the serological characteristics of PBC. Moreover, it provides information regarding the natural history of PBC, particularly on the long latency time for disease development.

Antibodies, Monoclonal↗
PubMed1997

Retinal artery and vein pressures in the dog and their relationship to aortic, intraocular, and cerebrospinal fluid pressures.

The relationship between retinal arterial (Pra) and aortic (Pa) pressures is unknown, and the relationship between retinal vein (Prv) pressure and intraocular pressure (IOP) is not clear. Also unclear is the effect of cerebrospinal fluid pressure (CSFp) upon retinal venous pressure. We aimed to measure the relationships among Pra, Prv, Pa, IOP, and CSFp. Dogs were anesthetized while IOP, CSFp, and Pa were monitored. Pipettes with 2.5-micron diameter tips, connected to a servonulling pressure transducer, were used to record pressures from the retinal arteries and veins. Across a range of IOP (16-22 mmHg), CSFp (0-21 mmHg), and Pa (23-195 mmHg) the Pra = 0.72 Pa + 4.3 (r = 0.99, n = 61, P < 0.01), which suggests that the relationship between Pra and Pa is linear over a broad range of systemic blood pressures. The correlation coefficient between Prv and IOP was greater than 0.96 (P < 0.01) at all venous sites and whether IOP was greater than or less than CSFp. The transmural pressure varied along the retinal vein from 1.3 +/- 0.3 mmHg (+/-95% CI, n = 30) at 1 disk diameter from the optic disk rim to 0.3 +/- 0.2 mmHg (n = 66) at the optic disk, with a 0.9-mmHg/mm pressure gradient. These are the first measurements demonstrating a retinal vein transmural pressure close to zero.

Animals↗
PubMed1997

Quantitative measurement of islet glucagon response to hypoglycemia by confocal fluorescence imaging in diabetic rats: effects of phlorizin treatment.

UNLABELLED: We have shown that the glucagon irresponsiveness to hypoglycemia in diabetic rats is markedly improved by correction of hyperglycemia independent of insulin. In contrast, normalization of glycemia by insulin did not improve this response. To find out whether these glucagon responses reflect changes in islet glucagon, we directly quantified glucagon area and content in each pancreatic islet by using fluorescent immunostaining and computerized image analysis with confocal laser scanning microscopy (CLSM). The pancreases were analyzed in four groups of rats. 1. Normal controls (NC, n = 4), streptozotocin (65 mg/kg) diabetic rats. 2. Diabetic untreated (DU, n = 4). 3. Diabetic Phlorizin-treated, (0.4 g/kg), twice daily for 4 d (DP, n = 4). 4. Diabetic insulin-treated, using sustained release (2-3 U/d) insulin implant for 5 d (DI, n = 4). Basal plasma glucose was 7.4 +/- 0.3 mM in NC, increased to 14.5 +/- 2.2 mM in DU, which was normalized in DP (5.5 +/- 0.5) and DI (6.7 +/- 0.8). Acute hypoglycemia (H) was induced by i.v. insulin injection. The rats were sacrificed 2 h after insulin injection and the pancreas was removed. By imaging with CLSM, we quantified: 1. Percent of glucagon containing A-cell area/islet area, 2. Fluorescence intensity per islet area, which indicated glucagon content in the islet. 3. Fluorescence intensity per glucagon area indicating glucagon concentration in A-cells. In NC, glucagon containing A cell area was 21 +/- 2% of the islet area, and glucagon intensity and concentration was 11 +/- 1 U and 36 +/- 3.0 U, respectively, in basal (O) state and did not change in (H). In DU, glucagon area increased 183% (O) and 166% (H), and islet glucagon intensity increased by 235% (O) (p < 0.05), but decreased to 135% in H. Glucagon area in DP and DI did not differ significantly from DU. However, hypoglycemia in DP increased glucagon intensity in islet further to 306% of normal control (p < 0.05), suggesting marked increase in glucagon content indicating increased synthesis. In contrast, DI compared to DP showed a decrease in glucagon intensity in islet (46 +/- 3, DP to 22 +/- 2 DI; p < 0.05) in (H) state. Glucagon concentration followed the same pattern as its intensity. CONCLUSION: 1. Increase in islet glucagon content in diabetic rats was associated with increase in glucagon containing A-cell area per islet. 2. Phlorizin-induced insulin independent correction of hyperglycemia increased glucagon content per islet in hypoglycemic state. This, in part, probably contributed to improved glucagon response to hypoglycemia observed earlier 3. Normalization of glycemia with insulin reduced glucagon content of each islet during hypoglycemia. This may explain, in part, unresponsiveness of glucagon to hypoglycemia often observed in insulin-dependent diabetes mellitus (IDDM) with intensive insulin therapy.

Animals↗
PubMed1997

Multiple sclerosis: an immune legacy?

The aetiology of multiple sclerosis suggests that its occurrence depends on a combination of factors, including viral infection in early childhood, genotype and an initiating event within the central nervous system. The resulting damage may be caused by events initiated by free radicals. Free radicals themselves may cause damage to myelin and also may trigger the arachidonic acid cascade, to produce compounds that are thought to initiate and augment T-cell activity. Repair of the damaged tissue is normally achieved by protective enzymes that remove damaged lipid from the myelin.

Antigens, Surface↗
PubMed1997

Inter-observer agreement in clinical optic disc measurement using a modified 60 D lens.

PURPOSE: To assess the inter-observer agreement of the measurement of optic disc dimensions by two observers using a modified 60 dioptre (D) fundus examination lens. METHOD: The vertical disc and cup diameters of 29 eyes were measured by two independent observers using a 60 D lens modified by incorporation of a 0.1 millimetre scale graticule. The vertical cup/disc ratio was calculated. Inter-observer agreement was assessed by calculation of the inter-observer differences and by the weighted kappa statistic. RESULTS: The two observers showed good agreement for the measurement of disc diameter (mean difference -0.04; range -0.04, 0.2) and for cup diameter (mean difference -0.03; range 0.3, 0.2). Closer agreement for the vertical cup/disc ratio was achieved (mean kappa 0.96; 95% confidence limits 0.90, 1.0). The 95% confidence limit for the mean inter-observer difference in cup/disc ratio was 0.11, suggesting that a change of > 0.1 in the assessment of the cup/disc ratio by this technique is significant at the 5% level. CONCLUSION: High inter-observer agreement of optic disc measurement can be achieved with this technique. The method has the potential to improve the clinical evaluation of the optic disc and the precision and accuracy of the clinical measurement of other fundal structures.

Equipment Design↗
PubMed1997

Optic disc haemorrhages and vascular abnormalities in a glaucoma population.

PURPOSE: To retrospectively examine the optic disc photographs of a glaucoma population for optic disc haemorrhages, vascular occlusions and vascular abnormalities. METHODS: The optic disc photographs of 906 eyes of glaucoma and suspect glaucoma patients were examined. Optic disc photographs were taken annually, where possible, with the follow-up period varying between 1 and 14 years duration (mean, 2.89). Glaucoma patients are regularly reviewed every 4-6 months and glaucoma suspects every 1-2 years, depending on the ophthalmologist. Low-tension glaucoma patients were reviewed more frequently (mean, every 2.6 months). The results of the findings were compared to a control group of 39 subjects with a mean follow-up period of 7 years, using Fisher's exact test. RESULTS: It was found that during the period under review, 7.4% (n = 67) of eyes had optic disc haemorrhages. The highest frequency of optic disc haemorrhages (37.5%) was found in the low tension glaucoma group (P = 0.0001) followed by 11% of primary open-angle glaucoma eyes (P = 0.03). In the normal group there were three eyes with optic disc haemorrhages and one with a disc collateral, which constitutes 5.1% vascular changes in this sub-group. Of the study eyes 2.8% had central retinal vein occlusions, 1.3% branch vein occlusion, 1.2% disc vessel abnormalities (loops) and 1.1% disc collaterals. Discrete nerve fibre layer haemorrhages and microaneurysms were found in 0.8% and 1.8% of eyes, respectively. CONCLUSIONS: A total of 16.8% of the eyes observed in this study had either disc haemorrhages or vascular changes. The underlying trend of vascular and haemorrhagic changes in glaucoma are demonstrated in this sample, which is in general agreement with previous studies. The high percentage of optic disc haemorrhages in low tension glaucoma is highlighted. The presence of microaneurysms and nerve fibre layer haemorrhages is interesting but of unknown significance.

Aneurysm↗
PubMed1997

Endocrine disruptors and reproductive development: a weight-of-evidence overview.

It is clear that the endocrine system presents a number of target sites for the induction of adverse effects by environmental agents (Fig. 1). There are numerous examples demonstrating that reproductive and developmental processes may be exquisitely sensitive to exposure and there are clear effects induced by presumed endocrine-disrupting chemicals in a variety of species. The concerns raised by studies of wildlife and humans place added significance on a better understanding of the myriad of effects attributed to endocrine disruptors. But there remains a large void between the study of relatively high exposure levels used in laboratory settings versus the relatively low levels found in the general environment. It is also equally clear that the term "endocrine disruption' has been applied to situations where the biological basis is far from conclusive. This may be a moot point in situations where populations are experiencing adverse effects on reproduction, but as scientists we must be vigilant of the appropriate use of descriptive terminology, particularly in cases where public awareness and concern are as great as this. Not only is there a need for better test procedures (both in vivo and in vitro) to characterize the potential of environmental agents to disrupt endocrine function in laboratory species, but there is also a need for a more comprehensive understanding of the normal physiological processes associated with reproduction and development in those wildlife species studied. At the same time, obtaining better information on the transport, fate and bioavailability of chemicals released into the environment remains an important but imposing task. The goals of risk characterization are to carefully delineate cause-and-effect relationships, define the dose-response relationships, and determine whether environmental exposures exceed acceptable levels. A concerted research effort is needed to fill the voids in our knowledge and reduce the large uncertainties that exist today. Only then can regulatory actions take place within the confines of legislative mandates, remediation strategies and considerations of international use and transport. Towards this end, the US Environmental Protection Agency (EPA) sponsored two workshops in 1995 (Ankley et al. 1996, Kavlock et al. 1996) at which groups of international scientists began the process of identifying research needs. Similar efforts also took place in several European countries at about the same time (Danish Environmental Protection Agency 1995, Medical Research Council 1995, Umweltbundesamt 1995). More recently, a Working Group on Endocrine Disruptors has been established within the Committee on the Environment and Natural Resources of the US Government's National Science and Technology Council. The objectives of this Working Group are to (1) formulate a framework for identifying research needs related to the health and ecological effects of endocrine-disrupting chemicals; (2) conduct an inventory of on-going federal research programs; and (3) identify research gaps and facilitate a co-ordinated research plan to address them. These efforts were largely completed in the Fall of 1996 and the information will be made available via the Internet (http;@www.cpa.gov/endocrine). The group also plans to work more broadly with other governments and private industry and public interest groups conducting research on this tissue to co-ordinate research and disseminate scientific information. Persons wishing to know more about this effort should contact the authors. The issue of endocrine disruption has raised the consciousness of many researchers, both within and outside the toxicology community, and has attracted considerable public and political interest. We now have the beginnings of international co-operation to identify the most important scientific uncertainties and to dedicate resources to address the critical gaps. (ABSTRACT TRUNCATED)

Adolescent↗
PubMed1996

Quantal release at visualized terminals of a crayfish motor axon: intraterminal and regional differences.

Synaptic transmission was measured at visualized terminal varicosities of the motor axon providing the sole excitatory innervation of the "opener" muscle in walking legs of crayfish (Procambarus clarkii Girard). Two questions were addressed: 1) How uniform is quantal emission at different locations along terminals innervating a single muscle fiber, and 2) can differences in quantal emission account for the different excitatory postsynaptic potential (EPSP) amplitudes generated by terminals localized in defined regions of the muscle? Extracellular "macropatch" electrodes were placed over individual varicosities, viewed after brief exposure to a fluorescent dye, and synaptic currents were recorded to determine quantal content of transmission. Along terminals supplying a single muscle fiber, nonuniform release was found: Varicosities closer to the point of origin of the terminal branch released more transmitter than those located more distally. Quantal content was higher for varicosities of the muscle's proximal region (where large EPSPs occur) than for varicosities of the central region (where small EPSPs occur). The probability of transmitter release per synapse is estimated to be greater for the proximal varicosities. At low frequencies of stimulation, quantal content per muscle fiber is two to four times larger in the proximal region. Taken in conjunction with a twofold higher mean input resistance for the proximal muscle fibers, the difference in quantal content can account for a four- to eightfold difference in EPSP amplitude. The observed mean EPSP amplitude is at least eight times larger in the proximal region. We discuss factors contributing to differences in EPSP amplitudes.

Animals↗
PubMed1996

Assessing ultrastructure of crustacean and insect neuromuscular junctions.

Motor nerve terminals of arthropods provide excellent models for study of synaptic transmission, and their ultrastructure can be investigated in the same endings from which physiological recordings have been obtained. An experimental procedure for marking a recording site for subsequent ultrastructural analysis is described. The most commonly used procedure for ultrastructural analysis has been serial sectioning and three-dimensional reconstruction. This procedure has the advantage of providing information about the entire nerve terminal, including quantitative information on number, sizes, and relative positions of individual synapses and presynaptic 'active zones'. However, several errors may be generated in the process of viewing the sections and making the reconstruction; these errors can in principle lead to overestimation of synapse and active zone size. The errors become relatively more serious for smaller structures. Procedures for alleviating some of the possible errors are outlined. It is desirable to have additional information from other methods, such as freeze-fracture replication, to guide analysis of reconstructions from serial sections. Combined physiological and ultrastructural analysis of arthropod terminals has shown that each terminal has many small synapses, differing in size and in number of active zones, and that in some terminals, many of the observed synapses have a very low probability of transmission when nerve impulses occur at low frequencies.

Animals↗
PubMed1996

Vinclozolin does not alter progesterone receptor (PR) function in vivo despite inhibition of PR binding by its metabolites in vitro.

Vinclozolin, a dicarboximide fungicide, alters morphological sex differentiation in male rats following perinatal exposure. The occurrence of these abnormalities correlates with the in vivo formation of two antiandrogenic metabolites of vinclozolin, (i.e. 2-[[(3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid (Mt) and 3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide (M2)), which are potent inhibitors of rat androgen receptor binding. As steroid hormone receptors exhibit promiscuity in their ability to bind different ligands, the present study evaluated the ability of these vinclozolin metabolites to bind to the estrogen (ER) and progesterone (PR) receptors in vitro, and to alter ER and PR function following in vivo exposure. To this end, in vitro ligand binding assays demonstrated that both M1 and M2 can compete with endogenous ligand for binding to the PR (Ki = 400 and 60 microM, respectively). In contrast, neither metabolite exhibited the ability to bind ER. Subsequent in vivo studies to evaluate the potential of vinclozolin to alter ER or PR function demonstrate that, (1) the estrogen-dependent increases in uterine weight and PR induction were not altered by vinclozolin; (2) the distribution of nuclear and cytosolic PR was not altered following short-term vinclozolin exposure; and (3) vinclozolin did not disrupt ovulation in cycling female rats. These studies indicate that although vinclozolin metabolites can compete for binding to the PR in vitro, concentrations of these metabolites do not reach sufficient levels to disrupt female reproductive function following short-term in vivo exposure to vinclozolin. In addition, these studies demonstrate the importance of correlating in vitro receptor binding data with in vivo studies in order to understand the physiological consequences of exposure to environmental toxicants.

Anilides↗
PubMed1996

Expression profiling of mRNA obtained from single identified crustacean motor neurons: determination of specificity of hybridization.

The purpose of this study was to determine if the technique of expression profiling would allow us to determine the changes in the abundance of certain mRNAs in identifiable, single neurons as a result of heightened electrical activity. In doing so we developed an approach to test the specificity of hybridization in expression profiling. Messenger RNA from single identified crayfish motor neurons was amplified by ligation-mediated reverse transcription PCR and hybridized by dot-blotting to 45 target cDNAs from different species. As a test of specificity, the hybridization was repeated using unlabelled cDNAs, the dots were excised, and the hybridized nucleic acids were re-amplified, cloned, and sequenced to confirm their identity. By cloning and sequencing the re-amplified product for each cDNA examined, one can determine the degree of background hybridization as compared to homologous hybridization. False positive results were also observed when a species-specific cDNA and highly stringent hybridization conditions were used. Our results demonstrate that ligation-mediated PCR is a useful technique for checking the specificity of expression profiling. This approach can easily be adapted to any situation when confirmation of the specificity of nucleic acid hybridization is required. During this study, part of a novel crayfish neuronal actin cDNA was cloned and sequenced.

Animals↗
PubMed1996

Synaptic structural complexity as a factor enhancing probability of calcium-mediated transmitter release.

1. In a model synaptic system, the excitatory neuromuscular junction of the freshwater crayfish, the nerve terminals possess synapses that vary in structural complexity, with numbers of active zones ranging from zero to five. Active zones on individual synapses show a wide range of separation distances. We tested the hypothesis that two active zones of a single synapse in close proximity can enhance the localized increase in free calcium ion concentration, thus enhancing the probability of neurotransmission at that synapse. We evaluated the increase in calcium ion concentration as a function of distance between adjacent active zones. 2. To test this hypothesis, a reaction-diffusion model for Ca2+ entering the presynaptic terminals was used. This test was used because 1) present measurement techniques are inadequate to resolve quantitatively the highly localized, transient calcium microdomains at synaptic active zones; and 2) there is presently no suitable preparation for physiological recording from isolated synapses with varying distances between active zones. Included in the model were intracellular buffer and a typical distribution of voltage-activated Ca2+ channels for an active zone, estimated from freeze-fracture micrographs. 3. The model indicated that localized Ca2+ clouds from discrete active zones can overlap to create spatial enhancement of Ca2+ concentration. The degree of interaction between two active zones depends on the distance between them. When two typical active zones are separated by < or = 200 nm, the maximum intracellular Ca2+ concentration ([Ca2+]i) is greater at 1) the midpoint between them, and 2) the center of each one, than at the corresponding positions for a single isolated active zone. Enhanced [Ca2+]i at the edge of the active zone where "docked" synaptic vesicles occur would be expected to have an effect on transmitter release. 4. When the model includes no intracellular buffer, the increase in [Ca2+]i is a linear function of calcium channel current, but is a nonlinear function of the number of conducting calcium channels in an active zone. With immobile buffer included, the increase in [Ca2+]i is nonlinear with respect to both channel current and number of conducting channels. 5. Inclusion of immobile buffer in the model provides "released" residual calcium that slowly accumulates during a train of current pulses. Released residual calcium accumulates more rapidly at paired active zones separated by < or = 200 nm that at single isolated active zones. 6. We propose that the probability of release is enhanced at synapses with closely associated active zones. Synapses of this type ("complex" synapses) could be selectively recruited when the neuron is active at low frequencies. At higher frequencies of neuronal activity, more distant active zones may interact and acquire a greater probability of releasing quanta. This would provide the nerve terminal with one component of a mechanism for frequency facilitation, because the number of quanta released by the terminal as a whole would increase with frequency. Thus variation in synaptic complexity in a nerve terminal provides a mechanism for short-term plasticity of transmitter release.

Animals↗