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At least 37 records · Page 2Linked to original sources

PubMed2006

Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission.

Abnormally synchronized synaptic transmission in the brain causes epilepsy. Most inherited forms of epilepsy result from mutations in ion channels. However, one form of epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF), is characterized by mutations in a secreted neuronal protein, LGI1. We show that ADAM22, a transmembrane protein that when mutated itself causes seizure, serves as a receptor for LGI1. LGI1 enhances AMPA receptor-mediated synaptic transmission in hippocampal slices. The mutated form of LGI1 fails to bind to ADAM22. ADAM22 is anchored to the postsynaptic density by cytoskeletal scaffolds containing stargazin. These studies in rat brain indicate possible avenues for understanding human epilepsy.

ADAM Proteins↗

PubMed2006

Termination and beyond: acetylcholinesterase as a modulator of synaptic transmission.

Termination of synaptic transmission by neurotransmitter hydrolysis is a substantial characteristic of cholinergic synapses. This unique termination mechanism makes acetylcholinesterase (AChE), the enzyme in charge of executing acetylcholine breakdown, a key component of cholinergic signaling. AChE is now known to exist not as a single entity, but rather as a combinatorial complex of protein products. The diverse AChE molecular forms are generated by a single gene that produces over ten different transcripts by alternative splicing and alternative promoter choices. These transcripts are translated into six different protein subunits. Mature AChE proteins are found as soluble monomers, amphipatic dimers, or tetramers of these subunits and become associated to the cellular membrane by specialized anchoring molecules or members of other heteromeric structural components. A substantial increasing body of research indicates that AChE functions in the central nervous system go far beyond the termination of synaptic transmission. The non-enzymatic neuromodulatory functions of AChE affect neurite outgrowth and synaptogenesis and play a major role in memory formation and stress responses. The structural homology between AChE and cell adhesion proteins, together with the recently discovered protein partners of AChE, predict the future unraveling of the molecular pathways underlying these multileveled functions.

Acetylcholine↗

PubMed2005

ATP hydrolysis is required for the rapid regulation of AMPA receptors during basal synaptic transmission and long-term synaptic plasticity.

ATP hydrolysis is critical for many cellular processes; however, the acute requirement for ATP hydrolysis in synaptic transmission and plasticity in neurons is unknown. Here we studied the effects of postsynaptically applying the non-hydrolyzable ATP analogue adenosine 5'-[beta,gamma-methylene]triphosphate (AMP-PCP) into hippocampal CA1 pyramidal cells in hippocampal slices. The effects of this manipulation were investigated on basal transmission and on two forms of long-term synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD). AMP-PCP caused an increase in basal AMPA receptor (AMPAR)-mediated transmission, which occurred rapidly within minutes of infusing the drug. This effect was selective for AMPARs, since pharmacologically isolated NMDAR-mediated synaptic currents did not exhibit this run up. In two-pathway experiments infusion of AMP-PCP blocked the induction of both LTD and LTP. These findings show an acute and selective role for ATP hydrolysis in regulating AMPAR function both during basal transmission and long-term synaptic plasticity. Recent evidence indicates that AMPARs are selectively and acutely regulated by the ATPase N-ethylmaleimide-sensitive factor (NSF), which forms part of a multi-protein complex with AMPARs. Our data are consistent with the idea that such a mechanism that can acutely bi-directionally regulate AMPAR function at synapses and requires ATP hydrolysis is necessary for rapid activity-dependent changes in synaptic strength.

Adenosine Triphosphate↗

PubMed1999

Doc2alpha is an activity-dependent modulator of excitatory synaptic transmission.

Doc2alpha is a synaptic vesicle-associated Ca2 + -binding protein. To study the role of Doc2alpha in synaptic transmission and modulation, we generated homozygous null Doc2alpha mutant mice. In the CA1 region of hippocampal slices in the mutant mice, excitatory synaptic responses evoked with prolonged 5 Hz stimulation showed a significantly larger frequency facilitation followed by a steeper depression than those in wild-type mice, whereas there was no difference in synaptic transmission at lower frequencies or in paired-pulse facilitation. These results suggest that Doc2alpha regulates synaptic transmission when high Ca2 + concentrations in the presynaptic terminal are sustained. Furthermore, the mutant mice showed impairment in long-term potentiation and passive avoidance task. Thus, Doc2alpha may regulate transmitter release during repetitive synaptic activation, thereby contributing to memory formation.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2004

VIP enhances both pre- and postsynaptic GABAergic transmission to hippocampal interneurones leading to increased excitatory synaptic transmission to CA1 pyramidal cells.

Vasoactive intestinal peptide (VIP) is present in the hippocampus in three subtypes of GABAergic interneurones, two of which innervate preferentially other interneurones, responsible for pyramidal cell inhibition. We investigated how pre- and postsynaptic modulation of GABAergic transmission (to both pyramidal cells and interneurones) by VIP could influence excitatory synaptic transmission in the CA1 area of the hippocampus. VIP (0.1-100 nM) increased [(3)H]GABA release from hippocampal synaptosomes (maximum effect at 1 nM VIP; 63.8 +/- 4.0%) but did not change [(3)H]glutamate release. VIP (0.3-30 nM) enhanced synaptic transmission in hippocampal slices (maximum effect at 1 nM VIP; field excitatory postsynaptic potentials (epsp) slope: 23.7 +/- 1.1%; population spike amplitude: 20.3 +/- 1.7%). The action on field epsp slope was fully dependent on GABAergic transmission since it was absent in the presence of picrotoxin (50 microM) plus CGP55845 (1 microM). VIP (1 nM) did not change paired-pulse facilitation but increased paired-pulse inhibition in CA1 pyramidal cells (16.0 +/- 0.9%), reinforcing the involvement of GABAergic transmission in the action of VIP. VIP (1 nM) increased muscimol-evoked inhibitory currents by 36.4 +/- 8.7% in eight out of ten CA1 interneurones in the stratum radiatum. This suggests that VIP promotes increased inhibition of interneurones that control pyramidal cells, leading to disinhibition of synaptic transmission to pyramidal cell dendrites. In conclusion, concerted pre- and postsynaptic actions of VIP lead to disinhibition of pyramidal cell dendrites causing an enhancement of synaptic transmission.

Animals↗

PubMed1991

Modulation of synaptic transmission in the retina.

Synaptic transmission between photoreceptors and horizontal cells can be modulated in at least two domains: amplitude and time. In teleost fish, synaptic transmission is modulated mainly in the amplitude domain. Cone-driven horizontal cells in this species require background illumination to maintain high light responsiveness, and they are strongly suppressed in prolonged darkness. Moreover, in light, cone horizontal cells are extensively coupled via gap junctions, and the coupling is reduced in strength after prolonged darkness. The dopaminergic interplexiform cells play a major role in the regulation of cone horizontal cell activity. They may release dopamine tonically in darkness, which suppresses the light responsiveness of horizontal cells and uncouples them. In amphibians, whose horizontal cells receive input from both rods and cones, the modulation appears to be in the time domain, i.e., the rise time of horizontal cell responses is slow in prolonged darkness and accelerated after background illumination. gamma-aminobutyric acid and glycine may mediate the changes in response rise time. Despite the differences of the neuromodulators involved, these species provide two complementary modes of modulation of synaptic transmission in the retina.

Animals↗

PubMed1997

Possible nicotinic receptor-mediated modulation of synaptic transmission in nucleus of the solitary tract.

Signal transmission from afferent nerves to neurons in the nucleus of the solitary tract (NTS) may be mediated partially by nicotinic acetylcholine receptors (nAChRs). Here, we investigated nAChR-mediated signal transmission using rat NTS slices. First, we characterized nAChRs by obtaining patch-clamp recordings from NTS neuronal cell bodies. Under whole cell voltage-clamp conditions at -60 mV, application of nicotine induced an inward current, and this effect was blocked by hexamethonium. In outside-out patch recordings, nicotine was seen to induce a hexamethonium-sensitive single-channel current. Second, we investigated nAChR-mediated signal transmission. Fast synaptic transmission mediated by nAChRs was not detected. The action of diffusible acetylcholine (ACh) on nAChRs was then tested using the outside-out patches excised from NTS neurons as probes for ACh. When the patch was placed at a distance of 20-30 microm from the cell body, single-channel currents were recorded, and these were inhibited by hexamethonium. The frequency of channel opening was increased by high-extracellular potassium concentration solution suggesting the voltage-dependent release ofACh that acts on nAChRs. These results suggested that nAChR-mediated signal transmission from sensory afferents to NTS neurons is in part mediated by diffusible ACh.

Acetylcholine↗

PubMed1983

Graded synaptic transmission between identified spiking neurons.

Graded synaptic transmission between spiking motoneurons of the pyloric group was studied in the stomatogastric ganglion of the spiny lobster, Panulirus interruptus. Intracellular microelectrodes were placed in the cell bodies of both pre- and postsynaptic neurons. Graded synaptic transmission was found between all tested cell pairs that were known to display spike-evoked synaptic transmission, including PD to LP, PD to PE, PD to PL, PL to LP, and LP to PD. Graded synaptic transmission was effective below the threshold for spikes. Thus, it was possible to study the influence of graded synaptic transmission in normally active ganglia without blockage of spikes by tetrodotoxin. PD and LP neurons that were known to produce spike-evoked inhibitory postsynaptic potentials (IPSPs) were also capable of producing inhibitory effects on postsynaptic cells below the threshold for spikes. When tetrodotoxin (TTX) was used to eliminate both spikes and endogenous membrane oscillations, depolarization of presynaptic neurons produced hyperpolarization of postsynaptic cells. The presynaptic response to a current step usually showed a small early peak and a maintained, slightly lower plateau. The postsynaptic response had a delay, then a rise to a pronounced peak, and a roughly exponential decline to a maintained plateau. There was a presynaptic voltage threshold for any postsynaptic response; beyond the threshold, both pre- and postsynaptic peak and plateau responses increased with increasing current. PD neurons normally are depolarized beyond their release threshold in tetrodotoxin and, thus, released transmitter tonically for the many-hour duration of these experiments. Chemical, tonic synaptic transmission, here called graded synaptic transmission, was demonstrated by the presence of the following criteria: 1) reversal in sign of the postsynaptic response, 2) synaptic delay, 3) reversal potential, 4) postsynaptic conductance increase, 5) graded and reversible block by reduction of external Ca2+, and 6) specific graded block of the LP-to-PD synapse without effect on the PD-to-LP synapse by less than 10 microM picrotoxin added to the bathing medium.

Action Potentials↗

PubMed1994

Absence of synaptotagmin disrupts excitation-secretion coupling during synaptic transmission.

Synaptotagmin is an integral synaptic vesicle protein proposed to be involved in Ca(2+)-dependent exocytosis during synaptic transmission. Null mutations in synaptotagmin have been made in Drosophila, and the protein's in vivo function has been assayed at the neuromuscular synapse. In the absence of synaptotagmin, synaptic transmission is dramatically impaired but is not abolished. In null mutants, evoked vesicle release is decreased by a factor of 10. Moreover, the fidelity of excitation-secretion coupling is impaired so that a given stimulus generates a more variable amount of secretion. However, this residual evoked release shows Ca(2+)-dependence similar to normal release, suggesting either that synaptotagmin is not the Ca2+ sensor or that a second, independent Ca2+ sensor exists. While evoked transmission is suppressed, the rate of spontaneous vesicle fusion is increased by a factor of 5. We conclude that synaptotagmin is not an absolutely essential component of the Ca(2+)-dependent secretion pathway in synaptic transmission but is necessary for normal levels of transmission. Our data support a model in which synaptotagmin functions as a negative regulator of spontaneous vesicle fusion and acts to increase the efficiency of excitation-secretion coupling during synaptic transmission.

Animals↗

PubMed1992

Neuronal excitability: voltage-dependent currents and synaptic transmission.

Neuronal membrane excitability and the synaptic connections among neurons produce behavior and cognition. The intracellular compartment of neurons is negatively charged relative to the extracellular space, and this charge, as well as current flow, is produced by ions. From the perspective of charged ions, the lipid bilayer of the neuronal membrane acts as a capacitor, and transmembrane glycoprotein pores or channels act as resistors. The open and closed states of ionic channels determine the membrane potential. At equilibrium, the lowest resistance or greatest permeability is for potassium, and the resting membrane potential is close to the equilibrium potential for potassium. When a channel is opened, permeable ions diffuse down their electrochemical gradients and the membrane potential is changed. Channels are gated (opened or closed) by voltage, neurotransmitters, and second messengers. The neuron integrates synaptic potentials produced by transmitter-gated channel activity and either generates a subthreshold potential, or a suprathreshold depolarization that generates an action potential or a burst of action potentials. Action potential generation is mediated by a large, brief sodium influx that is followed by activation of a voltage-dependent potassium eflux. The pattern of action potential firing is dependent on the interaction of a repertoire of voltage-dependent ion conductances. The action potential is the main signaling mechanism to activate synaptic transmission at axon terminals. Synaptic transmission is graded depending on the amount of calcium entering the presynaptic terminal. The number of action potentials, or the shape of the action potential, will determine the amount of calcium entering the terminal and the efficacy of synaptic transmission. Presynaptic ion channels may also be controlled by neurotransmitters or modulators and affect synaptic transmission by altering the amount of calcium influx.

Animals↗

PubMed1989

Altered synaptic transmission in Drosophila hyperkinetic mutants.

Synaptic transmission in Drosophila can be altered by mutations in specific genes. For example, mutations in the Shaker (Sh) gene, which encodes the rapidly inactivating A-type potassium channel, cause repetitive nerve firing and prolonged transmitter release at the neuromuscular junction. Here we show that mutations in the Hyperkinetic (Hk) gene also affect the properties of synaptic transmission at the neuromuscular junction. In particular, we find that whereas single or low frequency nerve stimulation evokes a wild type postsynaptic response, at higher frequencies of nerve stimulation, each stimulus results in repetitive nerve firing and increased postsynaptic response, which is similar to that observed in Sh mutants. Various experiments suggest that this increased postsynaptic response results from prolonged depolarization of the nerve terminal, leading to increased transmitter release at the neuromuscular junction. The similarity in phenotypes between Sh and Hk mutants, along with the observation that Sh is epistatic to Hk in its effects on synaptic transmission, suggest that Hk acts on synaptic transmission by an effect on A-type potassium channels.

Animals↗

PubMed2004

[Volatile anesthetics and synaptic transmission in the central nervous system].

Long-lasting changes in the synaptic efficacy of signaling between neurons in the central nervous system are thought to be involved in memory consolidation and recall. Such long-lasting changes were first demonstrated by Bliss et al. in 1973. They found that high frequency stimulation to the hippocampus produced an increase in the amplitude of excitatory postsynaptic potentials, which lasted at least for hours. This phenomenon is known as long-term potentiation (LTP). LTP occurs in many synaptic pathways, and some forms of LTP appear to be triggered by the influx of calcium through NMDA receptors. General anesthetics are thought to affect LTP, since clinically relevant concentrations of volatile anesthetics seem to modify ligand-gated ion channels such as glutamate receptors and GABA(A) receptors. Previous studies have shown that volatile anesthetics such as isoflurane and sevoflurane enhance GABA(A) receptor-mediated inhibition, suggesting that general anesthesia is produced, at least in part, by enhancing neural inhibition mediated by GABA(A) receptors. This review focuses on recent research concerning the effects of volatile anesthetics on synaptic transmission, synaptic plasticity, and clinically important diseases imparing synaptic transmission in the central nervous system.

Anesthetics, Inhalation↗

PubMed2003

Contribution of NR2B subunits to synaptic transmission in amygdaloid interneurons.

Synaptic responses of interneurons in the rat lateral amygdala (LA) to electrical microstimulation of putative cortical and thalamic afferents were studied in slice preparations in situ. The EPSPs at both thalamic and cortical inputs were composed of two major components that were sensitive to 6,7-dinitroxaline-2,3-dione and DL-2-amino-5-phosphonovaleric acid (APV), indicating mediation through AMPA and NMDA receptors. NMDA receptor activation contributed to basal synaptic transmission, as evidenced through a reduction of EPSP amplitudes and integrals by APV. NMDA receptor-mediated postsynaptic currents showed magnesium-regulated voltage dependence, and current-voltage relationships displayed a region of negative slope conductance negative to resting potential. Deactivation of NMDA receptor-mediated currents followed a two exponential time course, with both components being significantly reduced by ifenprodil (10 microm), an antagonist of the NR2B subunit of NMDA receptors. Significant differences were not observed between NMDA currents or ifenprodil effects at thalamic and cortical inputs. Furthermore, recordings from a sample of projection neurons in the LA provided additional evidence for the existence of ifenprodil-sensitive components of thalamically and cortically evoked NMDA receptor-mediated responses. Immunohistochemical double-labeling and combined in situ hybridization/immunohistochemistry demonstrated that GABA-immunoreactive as well as GABA-negative cells express the NR2B subunit. Overall, these results show that GABAergic interneurons in the LA express functional NMDA receptors, which participate in basal synaptic transmission at both thalamic and cortical inputs. The finding that NR2B subunits are critically involved in NMDA receptor-mediated signaling at the two major input pathways to interneurons and projection cells in the LA is particularly interesting in the light of previous observations that NR2B antagonists interfere with plastic changes in the LA related to associative fear conditioning.

Afferent Pathways↗

PubMed2006

Kainate receptor activation potentiates GABAergic synaptic transmission in the nucleus accumbens core.

Inhibitory synaptic transmission plays an important role in regulating the activity of medium spiny neurons (MSNs) in the nucleus accumbens (NAcc). The kainate (KA) subtype of ionotropic glutamate receptor has been shown to potently modulate GABAergic synaptic transmission in several brain regions. Although KA receptor subunits are expressed in the NAcc, KA receptor modulation of GABAergic synaptic transmission in this brain region has not been previously examined. In the current study, we sought to determine if KA receptor activation could alter inhibitory synaptic transmission in the NAcc as it has been shown to do in other brain regions. Using the whole cell patch-clamp technique, we demonstrate that KA receptor activation potentiates evoked GABAergic synaptic transmission and increases the frequency of spontaneous, but not miniature, GABA(A)-receptor-mediated IPSCs in the NAcc. In contrast, KA has no effect on currents evoked by exogenous application of GABA onto MSNs. Taken together, these data suggest that activation of KA receptors in the NAcc core potently facilitates action-potential-dependent GABAergic synaptic transmission, likely via an excitation of presynaptic GABAergic interneurons.

Animals↗

PubMed2006

TNF-alpha involves in altered prefrontal synaptic transmission in mice with persistent inflammatory pain.

Tumor necrosis factor alpha (TNF-alpha) is implicated in the development of persistent pain. Its expression increases both spinally and supraspinally after peripheral inflammation. The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in pain transmission and modulation. Prefrontal synaptic transmission is potentiated in mice with chronic pain through an enhancement of presynaptic transmitter release. However, it is not known if TNF-alpha expression is altered in the ACC in response to persistent pain and if synaptic transmission within this region is modulated by TNF-alpha. In the present study, we examined TNF-alpha expression in the mouse ACC following hind-paw administration of complete Freund's adjuvant (CFA) and examined the role of TNF-alpha in ACC synaptic transmission. Quantification of TNF-alpha at the protein level (by ELISA) revealed enhanced expression following CFA-induced peripheral inflammation. In vitro whole-cell patch-clamp recordings revealed that TNF-alpha significantly enhanced synaptic transmission through increased probability of neurotransmitter release in the ACC. Our findings provide evidence that presynaptic alterations caused by peripheral inflammation is partly attributable to the up-regulation of TNF-alpha in the ACC.

Animals↗

PubMed1980

Graded synaptic transmission between spiking neurons.

Graded synaptic transmission occurs between spiking neurons of the lobster stomatogastric ganglion. In addition to eliciting spike-evoked inhibitory potentials in postsynaptic cells, these neurons also release functionally significant amounts of transmitter below the threshold for action potentials. The spikeless postsynaptic potentials grade in amplitude with presynaptic voltage and can be maintained for long periods. Graded synaptic transmission can be modulated by synaptic input to the presynaptic neuron.

Action Potentials↗

PubMed2006

Overexpression of tau results in defective synaptic transmission in Drosophila neuromuscular junctions.

Synaptic dysfunction is believed to be an early pathological change in neurodegenerative diseases and may cause the earliest clinical symptoms. We have used Drosophila to model a tauopathy in order to analyse the earliest neuronal and synaptic dysfunction. Our work has shown that overexpression of human tau (0N3R) in larval motor neurons causes a disruption of axonal transport and a morphological and functional disruption of NMJs (neuromuscular junctions). Tau-expressing NMJs are smaller with an abnormal structure. Despite abnormal morphology, tau-expressing NMJs retain synaptotagmin expression and can form active zones. Tau-expressing NMJs are functionally abnormal and exhibit disrupted vesicle cycling and synaptic transmission. At low-frequency stimulation (1 Hz), ESPs (evoked synaptic potentials) produced by tau-expressing motor neurons were indistinguishable from wild-type; however, following high-frequency stimulation (50 Hz), ESPs from tau-expressing NMJs were significantly decreased in amplitude. To investigate the mechanism underlying the change in ESPs, we analysed the relative numbers and distribution of mitochondria. This revealed that motor neurons expressing tau had a significant reduction in the number of detectable mitochondria in the pre-synaptic terminal. Our results demonstrate that tau overexpression results in synaptic dysfunction, associated with a reduced complement of functional mitochondria. These findings suggest that disruption of axonal transport and synaptic transmission may be key components of the pathogenic mechanism that underlie neuronal dysfunction in the early stages of tauopathies.

Animals↗

PubMed1994

Long-lasting enhancement of NMDA receptor-mediated synaptic transmission by metabotropic glutamate receptor activation.

Synaptic transmission mediated by the N-methyl-D-aspartate (NMDA) glutamate receptor plays a key role in a range of plastic processes in the nervous system. These include long-term potentiation of synaptic transmission mediated by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor, neuronal development, excitotoxicity and certain learning tasks. Recently, long-term potentiation of NMDA receptor-mediated synaptic transmission was found to occur following high-frequency (tetanic) stimulation via an unknown mechanism. We show here that activation of metabotropic glutamate (mGlu) receptors by neurally released transmitter underlies this type of long-term potentiation. The whole-cell patch-clamp technique in the 'thick' slice of the rat dentate gyrus was used to measure NMDA receptor-mediated excitatory postsynaptic currents. We have found that mGlu receptor activation by a selective agonist produced a long-lasting enhancement which was mutually exclusive with long-term potentiation of these NMDA currents. Moreover, both forms of potentiation were greatly reduced by the mGlu receptor antagonists L-2-amino-3-phosphonopropionate and (R,S)-alpha-methyl-4-carboxyphenylglycine.

Animals↗