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Biomedical subjects

S M Thompson

Publications and source records attributed to S M Thompson.

At least 19 recordsLinked to original sources
PubMed2003

Identification of neutral mutants surrounding two naturally occurring variants of Potato spindle tuber viroid.

Single point mutations in the pathogenicity domain of Potato spindle tuber viroid (PSTVd) can have a dramatic effect on disease expression, and only three substitutions are required for the spontaneous conversion of the type strain PSTVd-Intermediate to the rapidly replicating, highly pathogenic variant RG1 (Gruner et al., Virology 209, 60-69, 1995). To identify available evolutionary pathways linking these two variants, we mutagenized five positions in an infectious cDNA copy of PSTVd-Intermediate and screened the resulting mixture of 768 sequences for neutral or near-neutral mutants. Numerical simulations based on the bioassay data indicate that the 23 variants recovered represent >80 % of all such sequences. RG1 was the only naturally occurring variant recovered, and the overall pattern of sequence changes observed indicates that PSTVd-Int occupies a comparatively steep peak within the fitness landscape.

Base Sequence↗
PubMed2001

Compartmentalized and binary behavior of terminal dendrites in hippocampal pyramidal neurons.

The dendritic arbor of pyramidal neurons is not a monolithic structure. We show here that the excitability of terminal apical dendrites differs from that of the apical trunk. In response to fluorescence-guided focal photolysis of caged glutamate, individual terminal apical dendrites generated cadmium-sensitive all-or-none responses that were subthreshold for somatic action potentials. Calcium transients produced by all-or-none responses were not restricted to the sites of photolysis, but occurred throughout individual distal dendritic compartments, indicating that electrogenesis is mediated primarily by voltage-gated calcium channels. Compartmentalized and binary behavior of parallel-connected terminal dendrites can greatly expand the computational power of a single neuron.

2-Amino-5-phosphonovalerate↗
PubMed2001

Metal-modified nucleobase sextet: joining four linear metal fragments (trans-a2PtII) and six model nucleobases to an exceedingly stable entity.

Crosslinking of three different model nucleobases (9-ethyladenine, 9-EtA; 9-ethylguanine, 9-EtGH; 1-methyluracil, 1-MeU) by two linear trans-aPtII (a = NH3 or CH3NH2) entities leads to a flat metal-modified base triplet, trans,trans-[(NH3)2Pt(1-MeU-N3)(mu-9-EtA-N7,N1)Pt(CH3NH2)2(9-EtGH-N7)]3+ (4b). Upon hemideprotonation of the 9-ethylguanine base at the N1 position. 4b spontaneously dimerizes to the metalated nucleobase sextet 5, [(4b)(triple bond)(4b-H)]5+. In this dimeric structure a neutral and an anionic guanine ligand, which are complementary to each other, are joined through three H bonds and additionally by two H bonds between guanine and uracil nucleobases. Four additional interbase H bonds maintain the approximate coplanarity of all six bases. The two base triplets form an exceedingly stable entity (KD = 500 +/- 150 M(-1) in DMSO), which is unprecedented in nucleobase chemistry. The precursor of 4b and several related complexes are described and their structures and solution properties are reported.

Base Pairing↗
PubMed2000

Differential control of GABA release at synapses from distinct interneurons in rat hippocampus.

1. Paired recordings from monosynaptically connected CA3 interneurons and pyramidal cells of rat hippocampal slice cultures were used to compare the modulation of GABA release at synapses from distinct interneurons. 2. The group II metabotropic glutamate receptor (mGluR) agonist (2S,2'R,3'R)-2-(2',3'-dicarboxylcyclopropyl) glycine (DCG-IV, 5 muM) reduced the amplitude of IPSPs originating from stratum radiatum but not stratum oriens interneurons. In contrast, the GABAB receptor agonist (-)baclofen (10 muM) reduced the amplitude of unitary IPSPs elicited by all interneurons. 3. IPSPs mediated by stratum oriens interneurons were unaffected by the N-type calcium channel blocker omega-conotoxin MVIIA (1 muM) but were suppressed by the P/Q-type blocker omega-agatoxin IVA (200 nM). In contrast, IPSPs mediated by stratum radiatum interneurons were abolished by omega-conotoxin MVIIA. 4. Transmission dynamics were different at synapses from the two groups of interneurons. IPSPs mediated by stratum oriens interneurons showed marked paired-pulse depression (PPD) at intervals of 50 400 ms. IPSPs mediated by stratum radiatum interneurons showed paired-pulse facilitation (PPF) at 50 ms and PPD at longer intervals. 5. The amplitude of unitary IPSPs from all interneurons was unaffected by the GABAB receptor antagonist CGP52432 (2 muM) as was PPD at both 50 and 400 ms intervals. However, CGP52432 did reduce PPD of extracellularly evoked IPSPs. 6. Our results show that two groups of inhibitory synapses impinging onto CA3 pyramidal cells can be distinguished according to their dynamic and modulatory properties.

Animals↗
PubMed2000

Synaptic plasticity: Building memories to last.

A series of recent studies has provided long-awaited direct evidence that enduring changes in synaptic strength, presumably underlying the formation of persistent memories, may be encoded in a lasting form as a change in synaptic structure.

Animals↗
PubMed1999

Heterogeneity of synaptic plasticity at unitary CA3-CA1 and CA3-CA3 connections in rat hippocampal slice cultures.

Long-term potentiation (LTP) of unitary EPSPs, generated by pairs of monosynaptically connected CA3 and CA1 pyramidal cells, was compared with LTP of extracellularly evoked, multi-unitary EPSPs in rat hippocampal slice cultures. LTP was induced by repeated, synchronous pairing of low-frequency presynaptic and postsynaptic activity. Three differences were observed. First, LTP of multi-unitary EPSPs displayed two phases: transient (<5 min) and sustained. Potentiation of unitary EPSPs displayed both phases in 42% of experiments; the remainder showed sustained potentiation only. Unitary EPSPs displaying transient-sustained and only sustained potentiation could be recorded from single postsynaptic cells, indicating that excitatory synapses on a given cell are heterogeneous with respect to short-term plasticity. Second, whereas LTP of multi-unitary EPSPs never resulted in greater than twofold increases in amplitude (mean potentiation of 175% of control), maximal LTP of unitary EPSPs was as great as 13-fold (mean potentiation of 250%). Third, LTP could not be induced in 24% of unitary EPSPs. We provide here the first evidence for the coexistence of potentiatable and nonpotentiatable synapses on individual postsynaptic neurons. Thirty-seven percent of connections not displaying LTP exhibited long-term depression (LTD), suggesting that the connections were already maximally potentiated. In the remaining 63% of these pairs, neither LTP nor LTD could be induced, despite the existence of a pharmacologically identified, NMDA receptor-mediated EPSP component. In conclusion, there is considerable heterogeneity in the amplitude and time course of LTP expression at different synaptic connections. A substantial proportion of apparently nonplastic synapses probably accounts for the weaker potentiation displayed by compound EPSPs.

Animals↗
PubMed1999

Selective glutamate receptor antagonists can induce or prevent axonal sprouting in rat hippocampal slice cultures.

After the transection of the Schaffer collateral pathway in hippocampal slice cultures, reactive sprouting is induced in the CA3 area, and eventually synaptic transmission between areas CA1 and CA3 is restored. Using this model, we have studied the role of ionotropic glutamate receptors in the initiation of axonal sprouting and the regeneration of functional synapses. We show that neither reactive sprouting nor functional recovery of synaptic transmission occur in the presence of the non-N-methyl-D-aspartate (NMDA) receptor antagonist 6-nitro-7-sulfamoylbenzoquinoxaline-2,3-dione (CNQX). In contrast, the NMDA receptor antagonists methyl-10, 11-dihydro-5-H-dibenzocyclohepten-5,10-imine (MK-801) or 3-(RS)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP) did not interfere with these processes. Moreover, we observed that the application of NMDA receptor antagonists induced massive axonal sprouting and an increase in the frequency of miniature excitatory postsynaptic currents in unlesioned cultures. Our results thus indicate that NMDA and non-NMDA receptors exert a differential effect on reactive sprouting and the recovery of synaptic transmission after injury in the hippocampus. Activation of non-NMDA receptors appears necessary for these processes to occur, whereas activation of NMDA receptors suppresses growth-associated protein -43 expression and axonal outgrowth.

Animals↗
PubMed1999

Activation of intrinsic hippocampal theta oscillations by acetylcholine in rat septo-hippocampal cocultures.

1. Oscillatory electro-encephalographic activity at theta frequencies (4-15 Hz) can be recorded from the hippocampus in vivo and depends on intact septal projections. The hypothesis that these oscillations are imposed on the hippocampus by rhythmically active septal inputs was tested using dual intracellular recordings from CA1 and CA3 pyramidal cells in septo-hippocampal cocultures. 2. Septo-hippocampal cocultures displayed spontaneous oscillatory synaptic activity at theta frequencies. In CA3 cells, EPSP/IPSP sequences predominated, whereas only EPSPs were apparent in CA1 cells. Synaptic potentials in CA3 cells preceded those in CA1 cells by 5-10 ms. 3. Oscillatory synaptic activity was blocked in cocultures by the muscarinic antagonist atropine (0.1 microM), facilitated but unchanged in frequency upon application of the acetylcholinesterase inhibitor neostigmine (1 microM), and not seen in hippocampal monocultures. 4. The muscarinic agonist methacholine (5-20 nM) induced oscillatory synaptic activity at 4-15 Hz in hippocampal monocultures, which was identical to that occurring spontaneously in septo-hippocampal cocultures. 5. Synaptic theta activity was observed in cocultures of septal tissue with subdissected hippocampal slices containing area CA3 alone, but not in septo-CA1 cocultures. 6. We conclude that oscillatory synaptic activity at theta frequencies, with similar characteristics to theta activity in vivo, can be generated by the hippocampal network in response to activation of muscarinic receptors by synaptically released acetylcholine from septal afferents. Furthermore, the oscillatory activity is determined by mechanisms intrinsic to the hippocampal circuitry, particularly area CA3. Rhythmic septal input is not required.

Acetylcholine↗
PubMed1999

Maternal phenylketonuria: a continuing problem.

OBJECTIVES: To estimate the number of women of childbearing age in New South Wales whose children are at risk of the maternal phenylketonuria (PKU) syndrome (intellectual disability, microcephaly, congenital malformations). SETTING: New South Wales, 1996. DESIGN: Comparison of number of women with PKU aged 15-44 years on the NSW PKU database (observed number) with expected number derived from population data. MAIN OUTCOME MEASURES: Observed and expected numbers of women with PKU (defined as blood phenylalanine levels > or = 400 mumol/L, and phenylalanine-restricted diet recommended) by age; number with no clinical contact with the PKU service in previous year; outcomes of pregnancies in women with PKU (January 1994 to July 1996). RESULTS: 110 women aged 15-44 years with PKU were listed on the database. The expected number was 145 (95% confidence interval, 122-171). The difference was greatest in the 30-44 years age group (born before comprehensive newborn screening), with only 55% of the expected number listed. Sixteen women who had been diagnosed with PKU at birth were not having regular follow-up, while 18 women had been diagnosed only after investigation of abnormalities in their children. Of 28 pregnancies managed by the NSW PKU service, 19 were considered unaffected by the maternal PKU syndrome and five affected (another three did not reach term; one outcome was unknown). Of 46 unmanaged pregnancies, all were affected. CONCLUSION: There is an urgent need for better follow-up of women with PKU and for education of health professionals about the MPKU syndrome, its recognition, the risks of untreated pregnancy and the benefits of dietary treatment.

Adolescent↗
PubMed1999

Miniature synaptic events maintain dendritic spines via AMPA receptor activation.

We investigated the influence of synaptically released glutamate on postsynaptic structure by comparing the effects of deafferentation, receptor antagonists and blockers of glutamate release in hippocampal slice cultures. CA1 pyramidal cell spine density and length decreased after transection of Schaffer collaterals and after application of AMPA receptor antagonists or botulinum toxin to unlesioned cultures. Loss of spines induced by lesion or by botulinum toxin was prevented by simultaneous AMPA application. Tetrodotoxin did not affect spine density. Synaptically released glutamate thus exerts a trophic effect on spines by acting at AMPA receptors. We conclude that AMPA receptor activation by spontaneous vesicular glutamate release is sufficient to maintain dendritic spines.

Afferent Pathways↗
PubMed1999

Excitatory synaptic transmission and its modulation by PKC is unchanged in the hippocampus of GAP-43-deficient mice.

We compared excitatory synaptic transmission between hippocampal pyramidal cells in dissociated hippocampal cell cultures and in area CA3 of hippocampal slice cultures derived from wild-type mice and mice with a genetic deletion of the presynaptic growth associated protein GAP-43. The basal frequency and amplitude of action potential-dependent and -independent spontaneous excitatory postsynaptic currents were similar in both groups. The probability that any two CA3 pyramidal cells in wild-type or GAP-43 knockout (-/-) slice cultures were synaptically connected was assessed with paired recordings and was not different. Furthermore, unitary synaptic responses were similar in the two genotypes. Bath application of phorbol 12,13-diacetate (0.6-3 microM) elicited a comparable increase in the frequency of miniature excitatory synaptic currents in wild-type and GAP-43 (-/-) cultures. This effect was blocked by the protein kinase C inhibitor, bisindolylmaleimide I (1.2 microM). Finally, 3 microM phorbol 12,13-diacetate potentiated the amplitude of unitary synaptic currents to a comparable extent in wild-type and GAP-43 (-/-) slice cultures. We conclude that GAP-43 is not required for normal excitatory synaptic transmission or the potentiation of presynaptic glutamate release mediated by activation of protein kinase C in the hippocampus.

Animals↗
PubMed1999

Development of liquid chromatography-electrospray ionization-tandem mass spectrometry methods for determination of urinary metabolites of benzene in humans.

To investigate the ways in which different levels of exposure affect the metabolic activation pathways of benzene in humans, and to examine the relationship between urinary metabolites and other biological markers, we have developed two sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays for quantitation of the benzene metabolites trans,transmuconic acid (t,t-MA), S-phenylmercapturic acid (S-PMA), hydroquinone (HQ), catechol (CAT), and for estimation of 1,2,4-trihydroxybenzene (BT). In our first assay, urinary S-PMA and t,t-MA were measured simultaneously by liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring (LC-ESI-MS/MS-SRM) in the negative ionization mode. In this assay, the metabolites [13C6]-S-PMA and [13C6]-t,t-MA were used as internal standards. The efficacy of this specific assay was evaluated in human urine specimens from 28 smokers and 18 nonsmokers serving as the benzene-exposed and nonexposed groups, respectively. The coefficient of variation (CV) of analyses on different days (n = 8) for S-PMA was 7% for samples containing 9.4 micrograms/L urine, and for t,t-MA was 10% for samples containing 0.07 mg/L. The mean levels of S-PMA and t,t-MA in smokers were 1.9-fold (p = 0.02) and 2.1-fold (p = 0.03) higher, respectively, than those in nonsmokers.

Acetylcysteine↗
PubMed1998

Long-term synaptic plasticity between pairs of individual CA3 pyramidal cells in rat hippocampal slice cultures.

1. Long-term potentiation (LTP) and depression (LTD) were investigated at synapses formed by pairs of monosynaptically connected CA3 pyramidal cells in rat hippocampal slice cultures. 2. An N-methyl-D-aspartate (NMDA) receptor-mediated component of the unitary EPSP, elicited at the resting membrane potential in response to single action potentials in an individual CA3 cell, could be isolated pharmacologically. 3. Associative LTP was induced when single presynaptic action potentials were repeatedly paired with 240 ms postsynaptic depolarizing pulses that evoked five to twelve action potentials or with single postsynaptic action potentials evoked near the peak of the unitary EPSP. LTP induction was prevented by an NMDA receptor antagonist. 4. Associative LTD was induced when single presynaptic action potentials were repeatedly elicited with a certain delay after either 240 ms postsynaptic depolarizing pulses or single postsynaptic action potentials. The time window within which presynaptic activity had to occur for LTD induction was dependent on the amount of postsynaptic depolarization. LTD was induced if single pre- and postsynaptic action potentials occurred synchronously. 5. Homosynaptic LTD was induced by 3 Hz tetanization of the presynaptic neuron for 3 min and was blocked by an NMDA receptor antagonist. 6. Depotentiation was produced with stimulation protocols that elicit either homosynaptic or associative LTD. 7. Recurrent excitatory synapses between CA3 cells display associative potentiation and depression. The sign of the change in synaptic strength is a function of the relative timing of pre- and postsynaptic action potentials.

Animals↗
PubMed1998

Utility of endoscopic biopsy samples to quantitate human duodenal ion transport.

Duodenal mucosal bicarbonate secretion (DMBS) prevents acid-peptic damage and facilitates nutrient absorption. DMBS is diminished in patients with duodenal ulcers and is normalized after Helicobacter pylori eradication. The measurement of DMBS in human patients in vivo requires intubation with a multi-lumen balloon tube and permits limited testing with putative agonists and antagonists. Our purpose was to develop a means to investigate transport events in human duodenal biopsy samples in vitro. After validation studies in a modified mini-Ussing chamber were performed, duodenal transport events were examined in proximal endoscopic biopsy samples from normal volunteers (n = 17). Tissues were mounted in modified mini-Ussing chambers (volume 2.5 ml, surface area 3.8 mm2). Short circuit current (Isc), potential difference (PD), and bicarbonate secretion were determined under basal conditions and after stimulation with graded doses of prostaglandin E2 (PGE2)(10(-8) to 10(-4) mol/L) and dibutyryl cAMP (db-cAMP)(10(-4) to 10(-2) mol/L). Duodenal tissues remained viable for at least 2 hours and exhibited stable basal HCO3(-) secretion and electrical parameters. Stimulation with PGE2 and db-cAMP resulted in dose-related increases in both Isc and HCO3(-) secretion (P < .05) that were abolished by ouabain and anoxia. It is concluded (1) that human duodenal bulb biopsy samples maintain their inherent transport function in mini-Ussing chambers and (2) that by using this novel method it will be possible to define the transport events that modulate human duodenal secretion, in particular bicarbonate secretion, in both health and disease.

Adult↗
PubMed1998

Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation.

OBJECTIVE: To reevaluate platelet serotonin (5-HT) levels in autism, measuring and controlling for effects of race and puberty. The specificity of hyperserotonemia for autism versus cognitive impairment is also assessed. METHOD: Platelet 5-HT levels were measured in 77 individuals, aged 2 through 37 years, with autistic disorder; 65 normal controls; and 22 mentally retarded or otherwise cognitively impaired (MR/CI) prepubertal children. Effects of diagnosis, race, and pubertal status were evaluated by analysis of variance in separate pre- and postpubertal groups. 5-HT levels were expressed as ng/mL blood and ng/microL platelet volume. RESULTS: Among prepubertal children, significant effects of diagnosis (ng/mL; F2,109 = 5.9, p = .004) and race (F2,109 = 14.7, p < .0005) were found. Autistic youngsters had significantly higher 5-HT concentrations than controls, although the elevation (25%) was less than typically reported; MR/CI children had levels very similar to those of controls. White children had significantly lower 5-HT levels than black or Latino youngsters, regardless of diagnosis. Diagnosis and race effects were nonsignificant in the postpubertal group. Postpubertal subjects had lower 5-HT concentrations than prepubertal subjects (ng/mL; F1,114 = 28.5, p < .0005). CONCLUSIONS: The data underscore the importance of matching for race and pubertal status in neuropsychiatric research and suggest that the prevalence of hyperserotonemia in autistic individuals may have been overestimated because of a failure to control for both variables. Hyperserotonemia was not found in MR/CI youngsters without autistic features.

Adolescent↗
PubMed1997

Ca2+ or Sr2+ partially rescues synaptic transmission in hippocampal cultures treated with botulinum toxin A and C, but not tetanus toxin.

Botulinum (BoNT/A-G) and tetanus toxins (TeNT) are zinc endopeptidases that cleave proteins associated with presynaptic terminals (SNAP-25, syntaxin, or VAMP/synaptobrevin) and block neurotransmitter release. Treatment of hippocampal slice cultures with BoNT/A, BoNT/C, BoNT/E, or TeNT prevented the occurrence of spontaneous or miniature EPSCs (sEPSCs or mEPSCs) as well as the [Ca2+]o-independent increase in their frequency induced by phorbol ester, 0.5 nM alpha-latrotoxin, or sucrose. [Ca2+]o-independent and -dependent release thus requires that the target proteins of clostridial neurotoxins be uncleaved. In contrast, significant increases in mEPSC frequency were produced in BoNT-treated, but not TeNT-treated, cultures by application of the Ca2+ ionophore ionomycin in the presence of 10 mM [Ca2+]o. The frequency of sEPSCs was increased in BoNT-treated, but not TeNT-treated, cultures by increasing [Ca2+]o from 2.8 to 5-10 mM or by applying 5 mM Sr2+. Large Ca2+ and Sr2+ influxes thus can rescue release after BoNT treatment, albeit less than in control cultures. The nature of the toxin-induced modification of Ca2+-dependent release was assessed by recordings from monosynaptically coupled CA3 cell pairs. The paired-pulse ratio of unitary EPSCs evoked by two presynaptic action potentials in close succession was 0.5 in control cultures, but it was 1.4 and 1.2 in BoNT/A- or BoNT/C-treated cultures when recorded in 10 mM [Ca2+]o. Log-log plots of unitary EPSC amplitude versus [Ca2+]o were shifted toward higher [Ca2+]o in BoNT/A- or BoNT/C-treated cultures, but their slope was unchanged and the maximal EPSC amplitudes were reduced. We conclude that BoNTs reduce the Ca2+ sensitivity of the exocytotic machinery and the number of quanta released.

Animals↗
PubMed1997

Action-potential propagation gated by an axonal I(A)-like K+ conductance in hippocampus.

Integration of membrane-potential changes is traditionally reserved for neuronal somatodendritic compartments. Axons are typically considered to transmit reliably the result of this integration, the action potential, to nerve terminals. By recording from pairs of pyramidal cells in hippocampal slice cultures, we show here that the propagation of action potentials to nerve terminals is impaired if presynaptic action potentials are preceded by brief or tonic hyperpolarization. Action-potential propagation fails only when the presynaptic action potential is triggered within the first 15-20ms of a depolarizing step from hyperpolarized potentials; action-potential propagation failures are blocked when presynaptic cells are impaled with electrodes containing 4-aminopyridine, indicating that a fast-inactivating, A-type K+ conductance is involved. Propagation failed between some, but not all, of the postsynaptic cells contacted by a single presynaptic cell, suggesting that the presynaptic action potentials failed at axonal branch points. We conclude that the physiological activation of an I(A)-like potassium conductance can locally block propagation of presynaptic action potentials in axons of the central nervous system. Thus axons do not always behave as simple electrical cables: their capacity to transmit action potentials is determined by a time-dependent integration of recent membrane-potential changes.

4-Aminopyridine↗