Biomedical subjects

G Lynch

Publications and source records attributed to G Lynch.

At least 181 records · Page 10Linked to original sources

PubMed1997

Sialic acid residues indirectly modulate the binding properties of AMPA-type glutamate receptors.

Manipulations that disrupt the extracellular interactions of neural cell adhesion molecules (NCAMs) block the formation of stable long-term potentiation (LTP) but do not reverse already established potentiation. Several studies have implicated a change in AMPA-type glutamate receptors as being responsible for the expression of LTP but there are no evident links between NCAMs and the receptors. NCAMs are major carriers of sialic acid residues in the brain and removal of these with neuraminidase markedly affects the binding properties of the adhesion molecules. Therefore, the present study tested if neuraminidase treatment produces a change in AMPA receptors. Preincubation of cortical membranes with the enzyme for 15 min at 37 degrees C caused a approximately 5% reduction in the apparent sizes of NCAMs 140 and 180 but had no detectable influence on the sizes of various glutamate receptor subunits. The same treatment resulted in a 20 +/- 1% increase in the binding of [3H]AMPA with no apparent effect on binding to NMDA-type glutamate receptors or to high affinity kainate receptors. In membranes from the hippocampus, neuraminidase induced a 30 +/- 2% increase in binding which Scatchard analyses showed to be due to an increase in receptor affinity. Finally, neuraminidase had no effect on either the binding properties of solubilized AMPA receptors or on AMPA receptors stably expressed in a non-neuronal cell line. These results: (i) demonstrate that modulation of the extracellular environment can influence the binding properties of AMPA receptors, (ii) indicate that sialic acid residues in the extracellular compartment of synapses exert a significant and indirect influence on AMPA receptors and, (iii) suggest a route whereby NCAMs and LTP could be linked.

Animals↗

PubMed1997

Arg-Gly-Asp-Ser-selective adhesion and the stabilization of long-term potentiation: pharmacological studies and the characterization of a candidate matrix receptor.

Peptides known to block the extracellular interactions of adhesion receptors belonging to a subclass of the integrin family were tested for their effects on the stabilization of long-term potentiation (LTP) in hippocampal slices. Theta burst stimulation delivered after infusions of Gly-Ala-Val-Ser-Thr-Ala (GAVSTA) resulted in a potentiation effect that decayed steadily over a period of 40 min; LTP elicited in the presence of inactive control peptides remained stable over this time period. GAVSTA had no detectible influence on baseline responses, induction processes, or the initial degree of potentiation. Infusions of integrin antagonists after application of theta bursts also resulted in the occurrence of a decremental form of LTP. Affinity chromatography was then used in an effort to identify targets of the structurally dissimilar integrin blockers that disrupt LTP stabilization. Both integrin antagonists Gly-Arg-Gly-Asp-Ser-Pro and GAVSTA eluted a major species of 55 kDa (synaptegrin-1) from GRGDSP-affinity columns that had been loaded with solubilized synaptic membranes; lesser concentrations of three polypeptides of approximately 20, 27, and 30 kDa were also collected. Synaptegrin-1 was labeled by antibodies to the RGDS-binding integrin alpha5beta1. In addition, the synaptegrin, as well as the 27 kDa, protein was found to copurify with pre- and postsynaptic markers during the isolation of forebrain synaptosomes. These results indicate that a matrix recognition event occurring several minutes after induction of LTP is a necessary step in the stabilization of potentiated synapses; they also identify an integrin-like matrix receptor of 55 kDa that may contribute to this event.

Animals↗

PubMed1997

HIV infection of macrophages and pathogenesis of AIDS dementia complex: interaction of the host cell and viral genotype.

AIDS dementia complex (ADC) develops in only a third of HIV-infected patients who progress to AIDS. Macrophages and microglial cells are the major cellular sites of productive HIV replication in brain. Using 11 blood isolates of HIV from asymptomatic patients there was marked variation in tropism and the level of productive infection in recently adherent monocytes and monocyte-derived macrophages cultured in vitro. However, less variation was seen with 19 blood isolates from advanced HIV infection and 11 postmortem tissue isolates from brain, cerebrospinal fluid, spleen, and lung. Newly adherent monocytes expressed CCR5 in all seven patients tested, consistent with their susceptibility to infection but not explaining the above variability. There is, also marked regional variability in neuropathology in the brain of patients with ADC. We have demonstrated that there was marked variation in the V3 sequences of HIV clones from different regions of the cortex of a patient with ADC, suggesting independent evolution of HIV replication in brain. Furthermore, production of the neurotoxin quinolinic acid from HIV-infected macrophages varied, depending on the host and source of HIV isolate. Hence variations in viral genotype, production by infected macrophages, and subsequent toxin production may contribute to the variability in neuropathology between individuals and between different regions of the brain in the same individual.

AIDS Dementia Complex↗

PubMed1997

Evidence that a positive modulator of AMPA-type glutamate receptors improves delayed recall in aged humans.

Elderly subjects (65-76 years) were tested for recall of nonsense syllables prior to and after oral administration of 1-(quinoxalin-6 ylcarbonyl)piperidine (CX516), a centrally active drug that enhances currents mediated by AMPA-type glutamate receptors. A significant and positive drug effect was found for delayed (5 min) recall at 75 min posttreatment; average scores for the highest dose group were more than twofold greater than for the placebo group. The drug had no evident influence on heart rate or self-assessment of several psychological variables.

Aged↗

PubMed1997

Enhancement by an ampakine of memory encoding in humans.

Acentrally active drug that enhances AMPA receptor-mediated currents was tested for its effects on memory in humans. Evidence for a positive influence on encoding was obtained in four tests: (i) visual associations, (ii) recognition of odors, (iii) acquisition of a visuospatial maze, and (iv) location and identity of playing cards. The drug did not improve scores in a task requiring cued recall of verbal information. The selectivity of drug effects on memory was confirmed using tests of visual recognition, motor performance, and general intellectual functioning. These results suggest that positive modulators of AMPA receptors selectively improve at least some aspects of memory.

Adult↗

PubMed1997

Triazolam impairs delayed recall but not acquisition of various everyday memory tasks in humans.

A double-blind test battery was administered to 24 human subjects (8 control, 16 drug) to assess the effects of 0.125 mg triazolam (oral) on memory encoding and retention across delay intervals ranging from seconds to 1 week after presentation. Although the drug reduced immediate psychomotor performance, it did not impair recall of previously learned information, nor did it significantly impair encoding of new information. The drug enhanced immediate recall of the location and identity of playing cards, without affecting 4-h delayed recall. The drug treatment impaired correct recall of object names after a delay of 20 min. At 4 h delay, the drug impaired olfactory recognition and free-recall of object names. At both 1 day and 1 week delay, the drug impaired recall of biographical information and correct identification of picture-photographer pair associations. The drug also impaired the daily improvement of the drug group as compared with the control group in a geometric puzzle solving task. The time course of these memory impairments compares well with the known effects of triazolam on long-term potentiation (LTP), a candidate biological mechanism underlying telencephalic memory formation and expression.

Adolescent↗

PubMed1997

A profile of the behavioral changes produced by facilitation of AMPA-type glutamate receptors.

A newly developed group of benzoylpiperidine drugs that enhance AMPA-receptor-gated currents ("ampakines") has been shown to improve memory encoding in rats across a variety of experimental paradigms. The present experiments were intended to i) provide a partial profile of the behavioral changes produced by ampakines, ii) test if two ampakines (BDP-12 and BDP-20) that differ significantly in their effects on AMPA receptor kinetics produce similar behavioral profiles, and iii) determine if physiological potency is reflected in behavioral potency. BDP-20 reduced two measures of exploratory activity in aged rats but increased speed of performance in a radial maze; the drug also caused substantially improved retention of spatial information. These results are similar to those obtained with BDP-12, an analog that differs from BDP-20 in its effects on ligand binding to the AMPA receptor and on the physiological responses of the receptors to glutamate. BDP-20 was approximately ten-fold more potent in behavioral effects than BDP-12, which agrees with the relative potencies of the two drugs as assessed with excised patches and excitatory synaptic responses. These findings indicate that ampakines, though differing in their effects on AMPA-receptor-mediated responses, have similar effects at the behavioral level.

Animals↗

PubMed1997

The effects of haloperidol on visual search, eye movements and psychomotor performance.

The effects of single doses of haloperidol (2, 4 and 6 mg) were compared with lorazepam 2.5 mg and placebo in 15 healthy subjects. Visual search strategy was measured, along with a range of psychomotor and eye movement tests. Patients with Parkinson's disease have been shown to exhibit a shift from parallel to serial processing in visual search, but we demonstrated that this does not occur following administration of either haloperidol or lorazepam. Haloperidol was detected by visual analogue rating scales and peak saccadic velocity, the latter being the more sensitive measure. Haloperidol had no statistically significant effect on smooth pursuit position error, velocity error or saccadic intrusions. Digit symbol substitution performance was clearly diminished by haloperidol, but there was no effect on the continuous attention test. Lorazepam decreased performance in all tests apart from saccadic latency.

Adolescent↗

PubMed1997

Bioavailability and metabolism of cidofovir following topical administration to rabbits.

The bioavailability and metabolism of the antiviral nucleotide analog cidofovir (HPMPC) were examined in New Zealand white rabbits following topical administration to normal and abraded skin. Male rabbits (four per group) received 14C-cidofovir (100 microCi/kg) intravenously (1 mg/kg) as a solution or topically (2 mg/animal) as a 1% w/w gel containing hydroxyethylcellulose (HEC) with or without propylene glycol (PG). The same PG/HEC formulation was applied topically to an abraded skin site in a fourth group of animals. All radioactivity detected in plasma and skin was accounted for by cidofovir. Plasma concentrations of radioactivity declined multiexponentially following intravenous administration, with a terminal half-life of 5.4 h. For intact skin, the absolute bioavailabilities of the HEC and PG/HEC formulations were 0.2 and 2.1%, respectively. For abraded skin, the bioavailability for the PG/HEC gel was 41%. Radioactivity in kidneys was attributed to cidofovir ( > 95%) and cyclic HPMPC. Concentrations in kidney following topical administration of cidofovir to normal skin were < 4% of those following intravenous dosing. Topical application of cidofovir to intact skin led to negligible systemic exposure to the drug. The topical bioavailability and hence the flux of cidofovir through intact skin was enhanced by the presence of PG in the formulation. Abrasion of the skin removed the principal barrier to absorption and led to significant systemic exposure to cidofovir.

Administration, Topical↗

PubMed1997

Comparison of the effects of an ampakine with those of methamphetamine on aggregate neuronal activity in cortex versus striatum.

The present study used in situ hybridization to c-fos mRNA to compare the effects of an 'ampakine' (a positive modulator of AMPA type glutamate receptors) with those of methamphetamine on the balance of aggregate neuronal activity in the cortex versus striatum. Methamphetamine (n = 11) induced a marked increase in c-fos mRNA in the dorsomedial quadrant of the striatum and a 21% smaller, but still reliable, increase in the ventrolateral quadrant. The drug also elevated c-fos mRNA levels in the ventral and medial segments of the orbitofrontal cortex but had no detectable effects in motor and somatosensory neocortices. The ampakine (n = 11) caused a near inverse pattern of changes; i.e. a sizable increase in somatosensory labeling and a significant decrease in striatal labeling with statistically insignificant effects in motor and orbitofrontal cortex. Within-rat cortical and striatal values were correlated in both the vehicle (n = 11) and ampakine groups, and appropriate comparisons established that the ampakine caused 27-55% increases in the ratio of cortical to striatal labeling. These results are in accord with the idea that facilitation of glutamatergic transmission has 'network level' effects that are opposite in nature to those resulting from enhanced dopaminergic transmission. The potential relevance of ampakines alone or in conjunction with dopamine antagonists for the treatment of schizophrenia is discussed.

Animals↗

PubMed1997

Stable expression of recombinant AMPA receptor subunits: binding affinities and effects of allosteric modulators.

Homomeric AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors (GluRs) were stably expressed in kidney cells from cDNAs encoding GluR1 flop, GluR2 flip, GluR2 flop, and GluR3 flop subunits. The recombinant receptors were of the expected size and showed functional properties in whole-cell recording as previously reported. [3H]AMPA binding to all subunits was increased to a similar extent by the chaotropic ion thiocyanate (SCN-). Significant differences were found in the Scatchard plots, however, which were linear and of high affinity for GluR1 and -3 receptors (K(D) values of 33 and 52 nM, respectively) but showed curvature for GluR2 receptors, indicating the presence of two components with distinct affinities. As with brain AMPA receptors, solubilization of GluR2 receptors reduced the number of lower-affinity sites and correspondingly increased the number of higher-affinity sites. The sulfhydryl reagent p-chloromercuriphenylsulfonic acid, which increases binding to brain receptors, produced only minor changes except in the case of GluR2 flip. These results indicate that GluR2, among the subunits examined here, most closely resembles the native AMPA receptors in brain membranes. [3H]AMPA binding was inhibited in a noncompetitive manner by two drugs that change the desensitization kinetics of the AMPA receptor. In agreement with physiological observations, the apparent affinity of cyclothiazide for GluR2 flip (EC50 = 7 microM) was higher than that for receptors made of flop subunits (49-130 microM). In contrast, BDP-37, a member of the benzamide family of drugs, exhibited a lower potency for GluR2 flip (58 microM) than for any of the flop isoforms (18-40 microM). These results predict that the action of centrally active AMPA-receptor modulators varies across brain regions depending on their flip/flop composition.

Allosteric Regulation↗

PubMed1996

Effects of an AMPA receptor modulator on methamphetamine-induced hyperactivity in rats.

The present study tested if a positive modulator of AMPA-type glutamate receptors would counteract the behavioral effects of a drug that enhances the release of dopamine. BDP-29, a compound shown to increase AMPA receptor-mediated synaptic responses in hippocampal slices, markedly attenuated the amount of stereotypic rearings seen in rats after methamphetamine injections. These results suggest that AMPA receptor modulators ameliorate certain aberrant, dopamine-related behaviors and hence may be of interest with regard to schizophrenia.

Animals↗

PubMed1996

Early and late components of AMPA-receptor mediated field potentials in hippocampal slices.

Field EPSPs were recorded from the CA1 region of hippocampal slices under conditions in which components of the responses other than those generated by AMPA-type glutamate receptors were blocked. Laminar profile analysis indicated that the resultant potentials had separable phases: an early and fast stage followed by a late and slow stage. The location of the fast response was sensitive to stimulation position in the stratum radiatum; i.e., distal stimulation elicited maximum, negative going potentials in the distal stratum radiatum while proximal stimulation recordings were maximal in the proximal segment. The distribution of the late component was largely independent of stimulation electrode position in stratum radiatum. Current source density analysis revealed that the late response had a source in the most distal dendrites (stratum moleculare) and a sink near the cell body layer. It was not accompanied by evident changes in membrane conductance and had a decay time constant similar to the membrane time constant. Stimulation of the afferents to the basal dendrites of the pyramidal cells also resulted in a late response which again had a source in stratum moleculare. These results strongly suggest that the magnitude and waveform of the late component of the AMPA receptor mediated field potential reflects the biophysical properties of the most distal branches of the dendritic arborization. The laminar analyses also show that the late potential is minimal in the mid-stratum radiatum and thus suggest that this site is most appropriate for investigations concerned with the waveform of the fast component of AMPA receptor mediated synaptic response.

Animals↗

PubMed1996

Effect of the AMPA receptor modulator IDRA 21 on LTP in hippocampal slices.

IDRA 21 (7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide) has been reported to modulate AMPA receptor kinetics and to improve memory in certain animal models. In the present study, its effects on synaptic transmission and long-term potentiation (LTP) were tested in hippocampal slices. IDRA 21 (500 microM) significantly increased the amplitude and halfwidth of field EPSPs. The drug did not affect monosynaptic IPSPs but enhanced disynaptically-induced feedforward IPSPs, presumably by acting on AMPA receptors on interneurons. At concentrations that facilitated synaptic transmission, IDRA 21 promoted the induction of LTP; i.e. full potentiation was obtained with stimulation paradigms that were only partially effective in the absence of drug. The results support the hypothesis that drugs which enhance AMPA receptor-mediated currents facilitate LTP.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1996

Response to repetitive stimulation of AMPA receptors in patches excised from fields CA1 and CA3 of the hippocampus.

Patches excised from fields CA1 and CA3 of the hippocampus were used to study AMPA receptor responses to repetitive application of brief pulses of agonist. AMPA receptors in field CA1 exhibited a larger degree of paired-pulse depression and a slower recovery rate from desensitization than those from CA3 patches. Responses became progressively smaller during a train of short pulses (4 at 100 Hz), an effect that was greater in CA1 than CA3 patches and that was blocked by a drug (cyclothiazide) that slows desensitization. Cyclothiazide also increased steady state currents during a long pulse of glutamate and had a lower EC50 for CA3 than CA1 AMPA receptors. These results suggest (i) that differences in the relative balance of flip vs. flop subunits affect the kinetic and pharmacological properties of AMPA receptors in vivo, and (ii) that the rate of recovery from desensitization may influence responses to the bursts of afferent activity commonly used to induce long-term potentiation.

Animals↗

PubMed1996

Relative concentrations and seizure-induced changes in mRNAs encoding three AMPA receptor subunits in hippocampus and cortex.

In situ hybridization was used to determine 1) the relative concentrations of mRNAs encoding different subunits of the alpha-amino 3-hydroxy-5-methyl-4- isoxazolepropionate receptor family in select regions of rat forebrain and 2) whether limbic seizures alter the balances of the subunit mRNAs. GluR1 and GluR2 mRNA levels were about equal and were much greater than GluR3 mRNA levels in the principal neurons of each hippocampal subdivision. Probable interneurons in hippocampal molecular layers had much higher levels of GluR1 mRNA than of either GluR2 or GluR3 mRNA. Pyramidal cell layers in neo- and paleocortex had a balance of mRNAs that was significantly different from the balance in hippocampus: GluR1 mRNA and GluR3 mRNA levels were about equal and were substantially lower than those of GluR2 mRNA. Lesion-induced limbic seizures caused transient changes in mRNA levels that were differentiated with regard to subunit and brain region. All three mRNAs were decreased in the pyramidal layers of cortex, and changes in hippocampal pyramidal cells were smaller. Seizure-induced changes in granule cells of the dentate gyrus differed from all other regions examined: GluR1 mRNA was reduced to a greater degree than GluR2 mRNA, whereas GluR3 mRNA content was markedly increased. These data strongly suggest that the subunit composition of alpha-amino 3-hydroxy-5-methyl-4-isoxazolepropionate receptors differs significantly between areas of the cortical telencephalon. Furthermore, the data indicate that aberrant patterns of physiological activity differentially influence the expression of subunit mRNAs in a region-specific and/or cell-type-specific manner.

Animals↗

PubMed1996

Distinct memory circuits composing the hippocampal region.

The very different anatomical designs of the adjacent circuitries of the cortico-hippocampal pathway, along with their somewhat different synaptic plasticity mechanisms, suggest a nearly serial pathway of distinct memory circuits each contributing its own specialized processing operation to overall hippocampal function. Modeling and formal theoretical analysis of the prominent anatomical design features of particular circuits (piriform/entorhinal cortex; hippocampal field CA3; hippocampal field CA1) are found to identify potential emergent function not readily arrived at in the absence of these formal models, and yet which once derived can be seen potentially to confer unique capabilities to an integrated hippocampal mechanism for processing memories during behavior.

Animals↗

PubMed1996

Facilitation of glutamate receptors reverses an age-associated memory impairment in rats.

The accuracy of memory for recent events is reported to decay between young adulthood and middle age in humans (Crook et al., 1990; Crook and West, 1990; Thomas et al., 1977) due to impairments in acquisition and/or retention (Craik, 1977; Huppert and Kopelman, 1989). Effects of this kind are also found in comparisons of middle-aged (12-18 months) vs. young adult (3 months) rats in tests requiring retention of recently sampled spatial cues (Kadar et al., 1990a; Kadar et al., 1990b; Goudsmit et al., 1990; Weiss and Thompson, 1991). The causes of such changes in memory processing are unknown but might be expected to involve age-related losses in forebrain glutamate receptors (Bahr et al., 1992; Magnusson and Cotman, 1993; Wenk et al., 1991); these receptors mediate fast excitatory transmission in many brain regions and play an essential role in the production of long-term potentiation (LTP), a form of synaptic plasticity that has been implicated in memory encoding (Landfield and Lynch, 1977; Moore et al., 1993). In the present communication we report results indicating that a drug that enhances AMPA-type glutamate receptors acts centrally to selectively increase hippocampal spatial cell firing and improves both acquisition performance and memory retention in middle-aged rats to levels equivalent to those found in young adult animals.

Age Factors↗