Biomedical subjects

S Alford

Publications and source records attributed to S Alford.

At least 19 recordsLinked to original sources

PubMed2000

Unraveling the mechanism for respiratory rhythm generation.

Breathing is generated by a neuronal network located within the caudal brainstem. One area of particular significance for respiratory rhythm generation is the pre-Bötzinger (preBotC) complex in the ventrolateral medulla. An important step towards understanding the cellular and network basis by which neurons within this region generate the respiratory rhythm was made in a recent study by Koshiya and Smith.(1) Using simultaneous image analysis and electrophysiological techniques these authors identified a discrete population of synaptically-coupled pacemaker neurons within the preBotC. They postulated that these neurons constitute the minimal essential network component (kernel) for generating the respiratory rhythm. BioEssays 22:6-9, 2000.

Animals↗

PubMed2000

Physiological activation of presynaptic metabotropic glutamate receptors increases intracellular calcium and glutamate release.

Activation of metabotropic glutamate receptors (mGluRs) has diverse effects on the functioning of vertebrate synapses. The cellular mechanisms that underlie these changes, however, are largely unknown. The role of presynaptic mGluRs in modulating Ca(2+) dynamics and regulating neurotransmitter release was investigated at the vestibulospinal-reticulospinal (VS-RS) synapse in the lamprey brain stem. Application of the specific Group I mGluRs antagonist 7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) reduced the amplitude of consecutive high-frequency evoked excitatory postsynaptic currents (EPSCs). A series of experiments using techniques of electrophysiology and calcium imaging were carried out to determine the cellular mechanisms by which this phenomenon occurs. Concentration-dependent increases in the pre- and postsynaptic [Ca(2+)](i) were seen with the application of mGluR agonists. Similarly, high-frequency stimulation of axons caused a Group I mGluR-dependent enhancement in presynaptic Ca(2+) transients. Application of mGluR agonist caused a depolarization of the presynaptic elements, while thapsigargin decreased the high-frequency stimulus- and agonist-induced rises in [Ca(2+)](i). These data suggest that both membrane depolarization and the release of Ca(2+) from intracellular stores potentially play a role in mGluR-induced Ca(2+) signaling. To determine the effect of this modulation of Ca(2+) dynamics on spontaneous glutamate release, miniature EPSCs were recorded from postsynaptic reticulospinal neurons. A potent Group I mGluR agonist, (S)-homoquisqualic acid, caused a large increase in the frequency of events. These results demonstrate the presence of presynaptic Group I mGluRs at the VS-RS synapse. Activation of these receptors leads to a rise in [Ca(2+)](i) and enhances the spontaneous and evoked release of glutamate. Taken together, these studies highlight the importance of synaptic activation of these facilitatory autoreceptors in both short-term plasticity and synaptic transmission.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1999

NMDA receptor-mediated control of presynaptic calcium and neurotransmitter release.

Before action potential-evoked Ca2+ transients, basal presynaptic Ca2+ concentration may profoundly affect the amplitude of subsequent neurotransmitter release. Reticulospinal axons of the lamprey spinal cord receive glutamatergic synaptic input. We have investigated the effect of this input on presynaptic Ca2+ concentrations and evoked release of neurotransmitter. Paired recordings were made between reticulospinal axons and the neurons that make axo-axonic synapses onto those axons. Both excitatory and inhibitory paired-cell responses were recorded in the axons. Excitatory synaptic inputs were blocked by the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM) and by the NMDA receptor antagonist 2-amino-5-phosphonopentanoate (AP-5; 50 microM). Application of NMDA evoked an increase in presynaptic Ca2+ in reticulospinal axons. Extracellular stimulation evoked Ca2+ transients in axons when applied either directly over the axon or lateral to the axons. Transients evoked by the two types of stimulation differed in magnitude and sensitivity to AP-5. Simultaneous microelectrode recordings from the axons during Ca2+ imaging revealed that stimulation of synaptic inputs directed to the axons evoked Ca2+ entry. By the use of paired-cell recordings between reticulospinal axons and their postsynaptic targets, NMDA receptor activation was shown to enhance evoked release of transmitter from the axons that received axoaxonic inputs. When the synaptic input to the axon was stimulated before eliciting an action potential in the axon, transmitter release from the axon was enhanced. We conclude that NMDA receptor-mediated input to reticulospinal axons increases basal Ca2+ within the axons and that this Ca2+ is sufficient to enhance release from the axons.

2-Amino-5-phosphonovalerate↗

PubMed1999

Imaging synaptic activity in intact brain and slices with FM1-43 in C. elegans, lamprey, and rat.

The fluorescent probe FM1-43 has been used extensively for imaging vesicle recycling; however, high nonspecific adsorption resulting in elevated background levels has precluded its use in certain tissues, notably brain slices. We have found that a sulfobutylated derivative of beta-cyclodextrin (ADVASEP-7) has a higher affinity for FM1-43 than the plasma membrane. ADVASEP-7 was used as a carrier to remove FM1-43 nonspecifically bound to the outer leaflet of the plasma membrane or extracellular molecules, significantly reducing background staining. This has enabled us to visualize synaptic vesicle recycling in the nematode C. elegans, intact lamprey spinal cord, and rat brain slices.

Animals↗

PubMed1998

Metabotropic glutamate receptor-mediated control of neurotransmitter release.

Presynaptic metabotropic glutamate receptors (mGluRs) modulate the release of transmitter from most central synapses. However, difficulties in recording from presynaptic structures has lead to an incomplete understanding of the mechanisms underlying these fundamental processes. By recording directly from presynaptic reticulospinal axons and postsynaptic motoneurons of the lamprey spinal cord, we have obtained electrophysiological and optical evidence that vertebrate presynaptic metabotropic glutamate receptors modulate neurotransmitter release at this synapse through two distinct mechanisms: (1) mGluR activation in the presynaptic terminal depresses transmitter release by activating a presynaptic K+ current, and (2) mGluR activation enhances transmitter release by amplifying the action potential-evoked presynaptic Ca2+ signal by rapidly releasing Ca2+ from intracellular stores in a Ca2+-dependent manner. Furthermore, this effect is mediated by physiological release of glutamate from the presynaptic terminals. These autoreceptor-mediated processes are likely to generate complex effects on transmitter release evoked by repetitive stimulation.

4-Aminopyridine↗

PubMed1998

Modulation of pre- and postsynaptic calcium dynamics by ionotropic glutamate receptors at a plastic synapse.

This study was conducted to assess the role of ionotropic glutamate receptors in the modulation of calcium dynamics on both sides of a vertebrate plastic synapse. Retrograde labeling of neuronal elements with high-affinity calcium-sensitive dyes was used in conjunction with confocal imaging techniques in an in vitro lamprey brain stem preparation. A prolonged calcium transient was measured both pre- and postsynaptically in response to a period of high-frequency ("tetanic") stimulation to the vestibulospinal-reticulospinal synapse. The ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM) and D,L-2-amino-5-phosphonopentanoate (D,L-AP5; 100 microM) reduced the calcium signal in both compartments of the synapse. The presynaptic D,L-AP5-sensitive component was enhanced markedly by the removal of Mg2+ from the superfusate. Increasing the extracellular stimulus intensity progressively augmented the presynaptic calcium signal, suggesting the recruitment of excitatory axo-axonic inputs onto these fibers. Further, the presence of an excitatory amino acid-mediated presynaptic potential underlying a component of the Ca2+ signal was demonstrated by electrophysiological recordings from vestibulospinal axons. Bath application of agonist, in the presence of tetrodotoxin (1 microM), confirmed the existence of N-methyl-D-aspartate receptors at the presynaptic element capable of modulating calcium levels. The postsynaptic Ca2+ response, which is known to be necessary for long-term potentiation (LTP) induction at this synapse, was localized to areas of the dendritic tree that correlated with the location of known synaptic inputs; thus the synaptically activated rise in postsynaptic calcium may confer the synapse specificity of LTP induction previously demonstrated. In summary, we have demonstrated the existence of physiologically activated presynaptic ionotropic glutamate receptors that are capable of modulating levels of intracellular calcium and have highlighted the importance of receptor-mediated increases in postsynaptic calcium for neuronal plasticity in the lamprey.

2-Amino-5-phosphonovalerate↗

PubMed1997

Glutamate receptor-mediated synaptic excitation in axons of the lamprey.

1. Spontaneous and evoked synaptic inputs were recorded in vitro in the axons of lamprey reticulospinal neurones. After isolation of the axon from its somata, synaptic inputs were recorded using microelectrode and whole-cell patch clamp recording techniques. 2. Single stimuli applied to the spinal cord elicited Ca(2+)-dependent synaptic potentials with short latencies in reticulospinal axons. These synaptic inputs are capable of summation and generate sufficient depolarization to raise the membrane potential beyond threshold to initiate action potentials. Action potential initiation in the absence of the cell body indicates that these axons show synaptic integration. 3. Both evoked and spontaneous responses comprise at least two components of synaptic drive: a slow component (rise time of 9.6 +/- 2.1 ms) with a reversal potential of -53 +/- 19 mV and a fast component (rise time as fast as 0.85 ms) with a reversal potential of 0.3 +/- 9.1 mV. The responses are Ca2+ dependent, and are blocked by the substitution of Ba2+ for Ca2+ in the saline solution. 4. The slow component of synaptic input was blocked by the gamma-aminobutyric acidA (GABAA) receptor antagonist bicuculline (5 microM). The fast component was blocked by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 6-cyano-7-nitroqinoxaline-2,3-dione (CNQX; 10 microM) in Ringer solution containing physiological concentrations of Mg2+. Following removal of Mg2+ from the superfusate a further excitatory component was identified that was blocked by application of the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoate (AP5; 100 microM). 5. Comparison of the kinetic properties and the voltage sensitivity of the isolated components of evoked and spontaneous synaptic activity indicate that these responses are mediated by similar synaptic inputs. 6. These results suggest that axons and presynaptic terminals receive excitatory and inhibitory ionotropic receptor-mediated inputs. Summation of these inputs is possible indicating that the axons act as sites of synaptic integration similar to the role previously attributed only to neuronal dendrites and somata.

Action Potentials↗

PubMed1995

Neurotransmitter release evoked by nerve impulses without Ca2+ entry through Ca2+ channels in frog motor nerve endings.

1. The requirement for extracellular Ca2+ in the process of evoked acetylcholine (ACh) release by nerve impulses was tested at endplates in frog skeletal muscle. Ca(2+)-containing lipid vesicles (Ca2+ liposomes) were used to elevate cytoplasmic Ca2+ concentrations under conditions in which Ca2+ entry from the extracellular fluid was prevented. 2. In an extracellular solution containing no added Ca2+ and 1 mM Mg2+ ('Ca(2+)-free' solution), Ca2+ liposomes promoted the synchronous release of ACh quanta, reflected electrophysiologically as endplate potentials (EPPs), in response to temporally isolated nerve impulses. 3. Motor nerve stimulation generated EPPs during superfusion with Ca2+ liposomes in Ca(2+)-free solutions containing the Ca2+ channel blocker Co2+ (1 mM), and the Ca2+ chelator EGTA (2 mM). As a physiological control for Ca2+ leakage from the liposomes to the extracellular fluid, the effect of Ca2+ liposomes on asynchronous evoked ACh release mediated by Ba2+ was examined. In contrast to the effects of 0.2-0.3 mM extracellular Ca2+, which generated EPPs but antagonized Ba(2+)-mediated asynchronous ACh release, Ca2+ liposomes generated EPPs but did not reduce asynchronous release mediated by Ba2+. The effects of Ca2+ liposomes were thus not due to leakage of Ca2+ from the liposome to the extracellular fluid. 4. Morphological studies using fluorescently labelled liposomes in conjunction with a confocal microscope demonstrate that lipid is transferred from the liposomes to nerve endings and liposomal contents are delivered to the nerve terminal cytoplasm. 5. The results suggest that when intracellular Ca2+ is elevated using liposomes as a vehicle, evoked ACh release can occur in the absence of Ca2+ entry via Ca2+ channels.

Acetylcholine↗

PubMed1995

Properties of transmission at a giant glutamatergic synapse in cerebellum: the mossy fiber-unipolar brush cell synapse.

1. The synaptic activation by mossy fibers (MFs) of unipolar brush cells (UBCs) in the vestibular cerebellum (nodulus and uvula) was examined using patch-clamp recording methods in thin, rat cerebellar slices with Lucifer yellow-filled pipettes for subsequent fluorescence microscopic verification of the cell morphology. 2. UBCs were distinguished from adjacent granule cells in thin cerebellar slices in the uvula and nodulus regions by their larger soma diameters and short dendritic brush, greater whole-cell capacitance, and a prolonged, biphasic excitatory postsynaptic current (EPSC) to stimulation of MFs. 3. Thin-section transmission electron micrographs of the MF-UBC synapse displayed an unusually extensive area of synaptic apposition estimated to measure 12-40 microns2. The majority of UBCs was innervated by a single MF. At high magnification, individual clusters of presynaptic vesicles could be discerned, separated by regions of presynaptic membrane lacking vesicles, but apposed to continuous regions of postsynaptic density. Thus, after release, transmitter diffusion from the synaptic cleft must traverse considerable stretches of postsynaptic membrane before escape into extracellular space. In contrast, MF-granule cell synapses in these cerebellar regions resembled glutamate synapses in other brain regions in that the total synaptic area measured < or = 4 microns2. These synaptic junctions were flanked by short stretches of unspecialized plasma membrane, providing a short (0.5 micron) diffusional path from the site of neurotransmitter release to a branch point of the extracellular space. 4. The MF-evoked EPSC in UBCs was composed of a fast (10-90% rise time: 0.70 ms) and slow (10-90% rise time: 395 ms; 10-90% decay time: 3.1 s) component. The fast component was blocked by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate (AMPA/KA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM) and displayed linear current-voltage (I-V) relations in the presence or absence of external magnesium. 5. The slow EPSC was also mediated by glutamate receptors, but in most neurons both AMPA/KA and N-methyl-D-aspartate (NMDA) receptors contributed to the slow EPSC, with the contribution of NMDA receptors predominating in the majority of cells. Consequently, although all cells displayed linear I-V relations in Mg(2+)-free saline, cells in which the slow EPSC was predominently mediated by NMDA receptors exhibited voltage-dependent rectification in the presence of external Mg2+ (1 mM). 6. With increasing postnatal age (10-30 d), the contribution made to the slow EPSC by NMDA receptors declined, with a reciprocal increase in the contribution being made by AMPA/KA receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1995

Long-term potentiation of glutamatergic pathways in the lamprey brainstem.

Plasticity of synaptic transmission has been investigated in the lamprey brainstem. In this preparation, neurons of the vestibular nuclei make monosynaptic connections to reticulospinal neurons of the posterior (PRRN) and middle (MRRN) rhombencephalic reticular nuclei. This glutamatergic projection shows a long-lasting enhancement in efficacy following a brief high frequency (50 Hz) train of stimuli (tetanus). Enhancement was found on the inputs from the octavomotorius intermediate (nOMI) and octavomotorius posterior (nOMP) nuclei to the reticulospinal neurons of the PRRN and MRRN, and persisted for the entire duration of the recordings. The enhancement was limited to the pathway that received tetanic stimulation for the inputs to any given reticulospinal neuron. It depended upon the activation of postsynaptic processes at least in part; dialysis of the reticulospinal neuron by recording with a whole-cell patch pipette prevented its induction. This dialysis-dependent abolition of enhancement was shown to be dependent on a change in Ca2+ concentration in the postsynaptic neuron. The enhancement was not affected by blockade of NMDA receptors with D,L-2-amino-5-phosphonopentanoate (AP5) but was prevented by the metabotropic glutamate receptor (mGluR) antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG). In conclusion, this study demonstrates that vestibular inputs to reticulospinal neurons are capable of undergoing long-term potentiation (LTP) and that this LTP shows synapse specificity. Furthermore, this LTP is activated by synaptic stimulation of a subtype of the m-GluR family and its induction is mediated by changing Ca2+ concentrations in the postsynaptic neuron.

Animals↗

PubMed1993

Glutamate metabotropic receptor mediated depression of synaptic inputs to lamprey reticulospinal neurones.

The transmission of vestibular inputs to reticulospinal (RS) neurones of the posterior rhombencephalic nucleus (PRRN) has been shown to be depressed by the bath application of N-methyl-D-aspartate (NMDA). The aim of this study was to investigate the pharmacological mechanism involved using patch clamp recordings of reticulospinal neurones. It is demonstrated that the chemical component of vestibular inputs to the PRRN is mediated by glutamatergic synapses utilising alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors on the PRRN neurones. Monosynaptic excitatory postsynaptic currents (EPSCs) from octavomotorius relay cells to RS neurones are markedly depressed by the application of NMDA, a depression which was insensitive to competitive and non-competitive NMDA receptor antagonists. The effect of NMDA was eliminated by inactivation of G proteins. A similar depressive effect was observed following application of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) to the superfusate. It is concluded that NMDA acts at a metabotropic receptor located most likely presynaptically to reticulospinal neurones on terminals of octavomotorius relay cells.

2-Amino-5-phosphonovalerate↗

PubMed1993

Metabotropic glutamate receptors and calcium signalling in dendrites of hippocampal CA1 neurones.

We have combined patch-clamp recording with confocal microscopy to investigate how the synaptic activation of metabotropic glutamate receptors (mGluRs) may participate in the modulation of intracellular free calcium (Ca2+) in the dendrites of single CA1 pyramidal neurones, within hippocampal slices. Tetanic stimulation (100 Hz, 1 sec) of the Schaffer collateral-commissural pathway led to a transient rise in Ca2+ in the dendrites of neurones voltage- clamped at -35 mV, as determined using the fluorescent indicator fluo-3. The specific mGluR antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG), applied at a concentration of 250 or 500 microM, reduced the size of the Ca2+ transient whilst either producing a small reduction or, more commonly, having no effect on the synaptic current evoked by the tetanus. These data suggest that the synaptic activation of mGluRs can contribute to Ca2+ signalling in hippocampal neurones.

2-Amino-5-phosphonovalerate↗

PubMed1993

Characterization of Ca2+ signals induced in hippocampal CA1 neurones by the synaptic activation of NMDA receptors.

1. A combination of confocal microscopy, whole-cell patch-clamp recording, intracellular dialysis and pharmacological techniques have been employed to study Ca2+ signalling in CA1 pyramidal neurones, within rat hippocampal slices. 2. In the soma of CA1 neurones, depolarizing steps applied through the patch-pipette resulted in transient increases in the fluorescence emitted by the Ca2+ indicator fluo-3. The intensity of the fluorescence transients was proportional to the magnitude of the Ca2+ currents recorded through the pipette. Both the somatic fluorescence transients and the voltage-activated Ca2+ currents ran down in parallel over a period of between approximately 15-45 min. The fluorescence transients were considered, therefore, to be caused by increases in cytosolic free Ca2+. 3. Under current-clamp conditions, high-frequency (tetanic) stimulation (100 Hz, 1 s) of the Schaffer collateral-commissural pathway led to compound excitatory postsynaptic potentials (EPSPs) and somatic Ca2+ transients. The somatic Ca2+ transients were sensitive to the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonopentanoate (AP5; 100 microM). These transients, but not the EPSPs, disappeared with a time course similar to that of the run-down of voltage-gated Ca2+ currents. Tetanus-induced somatic Ca2+ transients could not be elicited under voltage-clamp conditions. 4. Fluorescence images were obtained from the dendrites of CA1 pyramidal neurones starting at least 30 min after obtaining whole-cell access to the neurone. Measurements were obtained only after voltage-gated Ca2+ channel activity had run down completely. 5. Tetanic stimulation of the Schaffer collateral-commissural pathway resulted in compound EPSPs and excitatory postsynaptic currents (EPSCs), under current- and voltage-clamp, respectively. In both cases, these were invariably associated with dendritic Ca2+ transients. In cells voltage-clamped at -35 mV, the fluorescent signal increased on average 2-fold during the tetanus and decayed to baseline values with a half-time (t1/2) of approximately 5 s. 6. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM) partially reduced the tetanus-induced EPSC without affecting the Ca2+ transients. In contrast, AP5, which also depressed the EPSC, substantially reduced or eliminated the Ca2+ transients. 7. In normal (i.e. 1 mM Mg(2+)-containing) medium, NMDA receptor-mediated synaptic currents displayed the typical region of negative slope conductance in the peak I-V relationship (between -90 and -35 mV). The dendritic tetanus-induced Ca2+ transients also displayed a similar anomalous voltage dependence, decreasing in size from -35 to -90 mV.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

The synaptic activation of NMDA receptors and Ca2+ signalling in neurons.

Long-term potentiation (LTP) in the hippocampus is a model system for understanding the synaptic basis of learning and memory. We have studied the mechanism of induction of LTP using voltage-clamp techniques and confocal imaging of Ca2+ in rat hippocampal slices. In the Schaffer collateral-commissural pathway the neurotransmitter L-glutamate activates two classes of ionotropic receptor, named after the selective ligands AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and NMDA (N-methyl-D-aspartate). During low frequency transmission the excitatory postsynaptic potential (EPSP) is mediated predominantly by AMPA receptors. NMDA receptors play a minor role because their ion channels are substantially blocked by Mg2+, and this block is intensified by GABA-mediated synaptic inhibition. During high frequency transmission the GABA-mediated inhibition is depressed, by mechanisms initiated by GABAB autoreceptors. This allows a greater contribution from the NMDA receptors, through which Ca2+ enters the dendrites of the postsynaptic neurons to initiate a cascade of biochemical processes which ultimately result in enhanced synaptic efficiency.

Animals↗

PubMed1991

Co-localized GABA and somatostatin use different ionic mechanisms to hyperpolarize target neurons in the lamprey spinal cord.

gamma-Aminobutyric acid (GABA) and somatostatin are co-localized in cells close to the central canal in the lamprey. These cells project to the lateral margin of the spinal cord where they form a GABA and somatostatin containing plexus. Stretch receptor neurons (edge cells) are situated along the lateral margin of the spinal cord and their dendrites extend into the GABA and somatostatin containing plexus. To investigate whether GABA and/or somatostatin exert an affect on edge cells, these putative transmitters were applied from extracellular pipettes onto edge cells during intracellular recordings. Both GABA and somatostatin hyperpolarized the edge cells but through different ionic mechanisms. GABA activated a chloride current while somatostatin activated a current most likely carried by potassium which, however, could not be blocked by any of the conventional potassium blockers.

Animals↗

PubMed1991

Long-term potentiation of NMDA receptor-mediated synaptic transmission in the hippocampus.

Neurotransmission at most excitatory synapses in the brain operates through two types of glutamate receptor termed alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors; these mediate the fast and slow components of excitatory postsynaptic potentials respectively. Activation of NMDA receptors can also lead to a long-lasting modification in synaptic efficiency at glutamatergic synapses; this is exemplified in the CA1 region of the hippocampus, where NMDA receptors mediate the induction of long-term potentiation (LTP). It is believed that in this region LTP is maintained by a specific increase in the AMPA receptor-mediated component of synaptic transmission. We now report, however, that a pharmacologically isolated NMDA receptor-mediated synaptic response can undergo robust, synapse-specific LTP. This finding has implications for neuropathologies such as epilepsy and neurodegeneration, in which excessive NMDA receptor activation has been implicated. It adds fundamentally to theories of synaptic plasticity because NMDA receptor activation may, in addition to causing increased synaptic efficiency, directly alter the plasticity of synapses.

Animals↗

PubMed1991

The involvement of GABAB receptors and coupled G-proteins in spinal GABAergic presynaptic inhibition.

GABA acts as a presynaptic inhibitory transmitter in the spinal cord. In the lamprey, it has recently been shown that it acts in this way at both primary sensory and motor system synapses and is important in the generation of a locomotor rhythm. Both GABAA and GABAB receptors are activated at these sites by GABA released during physiological activity. In some systems, GABAB receptor activation has been shown to lead to modulation of ion channel function indirectly through the action of a pertussis toxin (PTX)-sensitive G-protein. Here we have studied the mechanism of action of the presynaptic GABAB receptor in this system. GABAB receptor activation leads to a decrease in axonal membrane impedance and also to a reduction in the axonal action potential duration. The ionic basis for this response remains unknown, though it is not, unlike the response to GABAA receptor activation, mediated by an increase in conductance to Cl-. The effects of GABAB receptor antagonism with phaclofen are mimicked by pretreatment of the spinal cord with PTX. Because this procedure inactivates certain classes of G-proteins, it seemed likely that the GABAB receptor-mediated effects are initiated via a presynaptic population of PTX-sensitive G-proteins. Experiments in which only presynaptic G-proteins were interfered with indicate that this is so. Stable analogs of GTP and GDP were used to activate permanently or to antagonize, respectively, the GTP binding site in the presynaptic component of these spinal synapses. We conclude that GABAB receptor-mediated synaptic suppression in the spinal cord is caused by GTP binding to presynaptic G-proteins linked to the GABAB receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Effects of bicuculline and strychnine on synaptic inputs to edge cells during fictive locomotion.

Edge cells are mechanoreceptive neurones located in the lateral tracts of the lamprey spinal cord. Phasic activation of these cells by lateral bending can entrain the activity of the locomotor central pattern generator. During fictive locomotion induced by bath-applied NMDLA (N-methyl-D,L-aspartate) or sensory stimulation, edge cells receive synaptic input. In this paper we provide evidence that the tonic inhibition received during sensory-induced fictive locomotion is glycinergic. We also show that during fictive locomotion induced by application of NMDLA to the spinal cord, bicuculline unveils phasic synaptic activity in edge cells. During sensory-evoked fictive locomotion, by contrast, only tonic synaptic activity is apparent in the presence of bicuculline.

Action Potentials↗