Showing papers on "Neurotransmission published in 1997"
TL;DR: Modeling work based on experimental measurements indicates that short-term depression of intracortical synapses provides a dynamic gain-control mechanism that allows equal percentage rate changes on rapidly and slowly firing afferents to produce equal postsynaptic responses.
Abstract: Cortical neurons receive synaptic inputs from thousands of afferents that fire action potentials at rates ranging from less than 1 hertz to more than 200 hertz. Both the number of afferents and their large dynamic range can mask changes in the spatial and temporal pattern of synaptic activity, limiting the ability of a cortical neuron to respond to its inputs. Modeling work based on experimental measurements indicates that short-term depression of intracortical synapses provides a dynamic gain-control mechanism that allows equal percentage rate changes on rapidly and slowly firing afferents to produce equal postsynaptic responses. Unlike inhibitory and adaptive mechanisms that reduce responsiveness to all inputs, synaptic depression is input-specific, leading to a dramatic increase in the sensitivity of a neuron to subtle changes in the firing patterns of its afferents.
1,724 citations
TL;DR: The findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, thereby stimulating postsynaptic non-NMDA glutamate receptors.
Abstract: Subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal lobe-sensitive tests. Several lines of evidence suggest that ketamine may impair PFC function in part by interacting with dopamine neurotransmission in this region. This study sought to determine the mechanism by which ketamine may disrupt dopaminergic neurotransmission in, and cognitive functions associated with, the PFC. A thorough dose-response study using microdialysis in conscious rats indicated that low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate outflow in the PFC, suggesting that at these doses ketamine may increase glutamatergic neurotransmission in the PFC at non-NMDA glutamate receptors. An anesthetic dose of ketamine (200 mg/kg) decreased, and an intermediate dose of 50 mg/kg did not affect, glutamate levels. Ketamine, at 30 mg/kg, also increased the release of dopamine in the PFC. This increase was blocked by intra-PFC application of the AMPA/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione CNQX. Furthermore, ketamine-induced activation of dopamine release and impairment of spatial delayed alternation in the rodent, a PFC-sensitive cognitive task, was ameliorated by systemic pretreatment with AMPA/kainate receptor antagonist LY293558. These findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, thereby stimulating postsynaptic non-NMDA glutamate receptors.
1,697 citations
TL;DR: In this article, a wide range of rates of synaptic depression between different pairs of pyramidal neurons was found, suggesting that the relative contribution of rate and temporal signals varies along a continuum.
Abstract: Although signaling between neurons is central to the functioning of the brain, we still do not understand how the code used in signaling depends on the properties of synaptic transmission. Theoretical analysis combined with patch clamp recordings from pairs of neocortical pyramidal neurons revealed that the rate of synaptic depression, which depends on the probability of neurotransmitter release, dictates the extent to which firing rate and temporal coherence of action potentials within a presynaptic population are signaled to the postsynaptic neuron. The postsynaptic response primarily reflects rates of firing when depression is slow and temporal coherence when depression is fast. A wide range of rates of synaptic depression between different pairs of pyramidal neurons was found, suggesting that the relative contribution of rate and temporal signals varies along a continuum. We conclude that by setting the rate of synaptic depression, release probability is an important factor in determining the neural code.
1,634 citations
TL;DR: It is shown that weak tetanic stimulation, which ordinarily leads only to early LTP, or repeated tetanization in the presence of protein-Synthesis inhibitors, each results in protein-synthesis-dependent late LTP; this indicates that the persistence of LTP depends not only on local events during its induction, but also on the prior activity of the neuron.
Abstract: Repeated stimulation of hippocampal neurons can induce an immediate and prolonged increase in synaptic strength that is called long-term potentiation (LTP)—the primary cellular model of memory in the mammalian brain1. An early phase of LTP (lasting less than three hours) can be dissociated from late-phase LTP by using inhibitors of transcription and translation2–8. Because protein synthesis occurs mainly in the cell body9–12, whereas LTP is input-specific, the question arises of how the synapse specificity of late LTP is achieved without elaborate intracellular protein trafficking. We propose that LTP initiates the creation of a short-lasting protein-synthesis-independent 'synaptic tag' at the potentiated synapse which sequesters the relevant protein(s) to establish late LTP. In support of this idea, we now show that weak tetanic stimulation, which ordinarily leads only to early LTP, or repeated tetanization in the presence of protein-synthesis inhibitors, each results in protein-synthesis-dependent late LTP, provided repeated tetanization has already been applied at another input to the same population of neurons. The synaptic tag decays in less than three hours. These findings indicate that the persistence of LTP depends not only on local events during its induction, but also on the prior activity of the neuron.
1,577 citations
TL;DR: Action potentials provide a synaptically controlled, associative signal to the dendrites for Hebbian modifications of synaptic strength and induced a robust LTP in CA1 neurons.
Abstract: The role of back-propagating dendritic action potentials in the induction of long-term potentiation (LTP) was investigated in CA1 neurons by means of dendritic patch recordings and simultaneous calcium imaging. Pairing of subthreshold excitatory postsynaptic potentials (EPSPs) with back-propagating action potentials resulted in an amplification of dendritic action potentials and evoked calcium influx near the site of synaptic input. This pairing also induced a robust LTP, which was reduced when EPSPs were paired with non-back-propagating action potentials or when stimuli were unpaired. Action potentials thus provide a synaptically controlled, associative signal to the dendrites for Hebbian modifications of synaptic strength.
1,337 citations
TL;DR: Nicotinic ACh receptors in the CNS are composed of a diverse array of subunits and have a range of pharmacological properties but despite the fact that they are ligand-gated cation channels, their physiological functions have not been determined.
1,285 citations
TL;DR: Subtype-specific antibodies were used for immunohistochemistry combined with lesioning of the three major hippocampal pathways to establish the precise localization of presynaptic mGluRs in the rat hippocampus, suggesting that transmitter release is differentially regulated by 2-amino-4-phosphonobutyrate-sensitive mGLURs in individual synapses on single axons according to the identity of postsynaptic neurons.
Abstract: Neurotransmission in the hippocampus is modulated variously through presynaptic metabotropic glutamate receptors (mGluRs). To establish the precise localization of presynaptic mGluRs in the rat hippocampus, we used subtype-specific antibodies for eight mGluRs (mGluR1–mGluR8) for immunohistochemistry combined with lesioning of the three major hippocampal pathways: the perforant path, mossy fiber, and Schaffer collateral. Immunoreactivity for group II (mGluR2) and group III (mGluR4a, mGluR7a, mGluR7b, and mGluR8) mGluRs was predominantly localized to presynaptic elements, whereas that for group I mGluRs (mGluR1 and mGluR5) was localized to postsynaptic elements. The medial perforant path was strongly immunoreactive for mGluR2 and mGluR7a throughout the hippocampus, and the lateral perforant path was prominently immunoreactive for mGluR8 in the dentate gyrus and CA3 area. The mossy fiber was labeled for mGluR2, mGluR7a, and mGluR7b, whereas the Schaffer collateral was labeled only for mGluR7a. Electron microscopy further revealed the spatial segregation of group II and group III mGluRs within presynaptic elements. Immunolabeling for the group III receptors was predominantly observed in presynaptic active zones of asymmetrical and symmetrical synapses, whereas that for the group II receptor (mGluR2) was found in preterminal rather than terminal portions of axons. Target cell-specific segregation of receptors, first reported for mGluR7a (Shigemoto et al., 1996), was also apparent for the other group III mGluRs, suggesting that transmitter release is differentially regulated by 2-amino-4-phosphonobutyrate-sensitive mGluRs in individual synapses on single axons according to the identity of postsynaptic neurons.
1,128 citations
TL;DR: Induction of LTP increased the phosphorus-32 labeling of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA-Rs), which mediate rapid excitatory synaptic transmission and provides a postsynaptic molecular mechanism for synaptic plasticity.
Abstract: Long-term potentiation (LTP), a cellular model of learning and memory, requires calcium-dependent protein kinases. Induction of LTP increased the phosphorus-32 labeling of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPA-Rs), which mediate rapid excitatory synaptic transmission. This AMPA-R phosphorylation appeared to be catalyzed by Ca2+- and calmodulin-dependent protein kinase II (CaM-KII): (i) it correlated with the activation and autophosphorylation of CaM-KII, (ii) it was blocked by the CaM-KII inhibitor KN-62, and (iii) its phosphorus-32 peptide map was the same as that of GluR1 coexpressed with activated CaM-KII in HEK-293 cells. This covalent modulation of AMPA-Rs in LTP provides a postsynaptic molecular mechanism for synaptic plasticity.
1,079 citations
TL;DR: A rat homologue of unc-47 is expressed by central GABA neurons and confers vesicular GABA transport in transfected cells with kinetics and substrate specificity similar to those previously reported for synaptic vesicles from the brain, and thus VGAT is the first of a new family of neurotransmitter transporters.
Abstract: Synaptic transmission involves the regulated exocytosis of vesicles filled with neurotransmitter. Classical transmitters are synthesized in the cytoplasm, and so must be transported into synaptic vesicles. Although the vesicular transporters for monoamines and acetylcholine have been identified, the proteins responsible for packaging the primary inhibitory and excitatory transmitters, γ-aminobutyric acid (GABA) and glutamate remain unknown1,2. Studies in the nematode Caenorhabditis elegans have implicated the gene unc-47 in the release of GABA3. Here we show that the sequence of unc-47 predicts a protein with ten transmembrane domains, that the gene is expressed by GABA neurons, and that the protein colocalizes with synaptic vesicles. Further, a rat homologue of unc-47 is expressed by central GABA neurons and confers vesicular GABA transport in transfected cells with kinetics and substrate specificity similar to those previously reported for synaptic vesicles from the brain. Comparison of this vesicular GABA transporter (VGAT) with a vesicular transporter for monoamines shows that there are differences in the bioenergetic dependence of transport, and these presumably account for the differences in structure. Thus VGAT is the first of a new family of neurotransmitter transporters.
837 citations
TL;DR: Developing neurons in culture form inefficient synapses that require glial signals to become fully functional, and the role of glial cells in synapse formation and function was studied in cultures of purified neurons from the rat central nervous system.
Abstract: In the developing nervous system, glial cells guide axons to their target areas, but it is unknown whether they help neurons to establish functional synaptic connections. The role of glial cells in synapse formation and function was studied in cultures of purified neurons from the rat central nervous system. In glia-free cultures, retinal ganglion cells formed synapses with normal ultrastructure but displayed little spontaneous synaptic activity and high failure rates in evoked synaptic transmission. In cocultures with neuroglia, the frequency and amplitude of spontaneous postsynaptic currents were potentiated by 70-fold and 5-fold, respectively, and fewer transmission failures occurred. Glial cells increased the action potential-independent quantal release by 12-fold without affecting neuronal survival. Thus, developing neurons in culture form inefficient synapses that require glial signals to become fully functional.
771 citations
TL;DR: It is shown that two types of inhibitory neurons in the cerebellar cortex fire spontaneously and regularly in the absence of synaptic input but generate an irregular firing pattern in the presence of tonic synaptic inhibition, suggesting that the time window for synaptic integration is a dynamic variable modulated by the level of Tonic inhibition.
TL;DR: It is proposed that Rim serves as a Rab3-dependent regulator of synaptic-vesicle fusion by forming a GTP-dependent complex between synaptic plasma membranes and docked synaptic vesicles.
Abstract: Rab3 is a neuronal GTP-binding protein that regulates fusion of synaptic vesicles and is essential for long-term potentiation of hippocampal mossy fibre synapses1,2,3,4,5 More than thirty Rab GTP-binding proteins are known to function in diverse membrane transport pathways, although their mechanisms of action are unclear We have now identified a putative Rab3-effector protein called Rim Rim is composed of an amino-terminal zinc-finger motif and carboxy-terminal PDZ and C2 domains It binds only to GTP (but not to GDP)-complexed Rab3, and interacts with no other Rab protein tested There is enrichment of Rab3 and Rim in neurons, where they have complementary distributions Rab3 is found only on synaptic vesicles, whereas Rim is localized to presynaptic active zones in conventional synapses, and to presynaptic ribbons in ribbon synapses Transfection of PC12 cells with the amino-terminal domains of Rim greatly enhances regulated exocytosis in a Rab3-dependent manner We propose that Rim serves as a Rab3-dependent regulator of synaptic-vesicle fusion by forming a GTP-dependent complex between synaptic plasma membranes and docked synaptic vesicles
TL;DR: Evidence at synapses suggests that inhibition of presynaptic voltage-dependent Ca2+ channels plays the major role inPresynaptic inhibition of elicited neurotransmitter release, and modulation of the release machinery might contribute to inhibition of elicit release.
TL;DR: Analysis of NR2 subunit gene expression in single characterized neurons of postnatal neocortex revealed that cells expressing NR2A subunit mRNA had faster NMDAR EPSCs than cells not expressing this subunit, regardless ofPostnatal age.
Abstract: NMDA receptors play important roles in learning and memory and in sculpting neural connections during development. After the period of peak cortical plasticity, NMDA receptor-mediated EPSCs (NMDAR EPSCs) decrease in duration. A likely mechanism for this change in NMDA receptor properties is the molecular alteration of NMDA receptor structure by regulation of NMDA receptor subunit gene expression. The four modulatory NMDAR2A-D (NR2A-D) NMDA receptor subunits are known to alter NMDA receptor properties, and the expression of these subunits is regulated developmentally. It is unclear, however, how the four NR2 subunits are expressed in individual neurons and which NR2 subunits are important to the regulation of NMDA receptor properties during development in vivo. Analysis of NR2 subunit gene expression in single characterized neurons of postnatal neocortex revealed that cells expressing NR2A subunit mRNA had faster NMDAR EPSCs than cells not expressing this subunit, regardless of postnatal age. Expression of NR2A subunit mRNA in cortical neurons at even low levels seemed sufficient to alter the NMDA receptor time course. The proportion of cells expressing NR2A and displaying fast NMDAR EPSCs increased developmentally, thus providing a molecular basis for the developmental change in mean NMDAR EPSC duration.
TL;DR: It is shown that MAPK translocates into the nucleus of the presynaptic but not the postsynaptic cell during 5-HT-induced long-term facilitation, which appears to be specifically recruited and necessary for the long- term form of facilitation.
TL;DR: In this article, it was shown that insulin increases the number of functional postsynaptic GABA(A) receptors, thereby increasing the amplitude of the GABA-A-receptor-mediated miniature inhibitory post-synaptic currents (mIPSCs) without altering their time course.
Abstract: Modification of synaptic strength in the mammalian central nervous system (CNS) occurs at both pre- and postsynaptic sites. However, because postsynaptic receptors are likely to be saturated by released transmitter, an increase in the number of active postsynaptic receptors may be a more efficient way of strengthening synaptic efficacy. But there has been no evidence for a rapid recruitment of neurotransmitter receptors to the postsynaptic membrane in the CNS. Here we report that insulin causes the type A gamma-aminobutyric acid (GABA[A]) receptor, the principal receptor that mediates synaptic inhibition in the CNS, to translocate rapidly from the intracellular compartment to the plasma membrane in transfected HEK 293 cells, and that this relocation requires the beta2 subunit of the GABA(A) receptor. In CNS neurons, insulin increases the expression of GABA(A) receptors on the postsynaptic and dendritic membranes. We found that insulin increases the number of functional postsynaptic GABA(A) receptors, thereby increasing the amplitude of the GABA(A)-receptor-mediated miniature inhibitory postsynaptic currents (mIPSCs) without altering their time course. These results provide evidence for a rapid recruitment of functional receptors to the postsynaptic plasma membrane, suggesting a fundamental mechanism for the generation of synaptic plasticity.
TL;DR: Three new classes of proteins have been identified in the postsynaptic density at glutamatergic synapses: the PSD-95 family, the NR2B subunit of the NMDA-type glutamate receptor, and densin-180, which might represent a new class of synaptic adhesion molecule.
TL;DR: The role of transporters in clearing free glutamate from the synaptic cleft was studied in rat CA1 hippocampal neurons cultured on glial microislands and it was concluded thatTransporters buffer glutamate in the synaptic Cleft.
Abstract: The role of transporters in clearing free glutamate from the synaptic cleft was studied in rat CA1 hippocampal neurons cultured on glial microislands. The time course of free glutamate in the cleft during a synaptic event was estimated by measuring the extent to which the rapidly dissociating AMPA receptor antagonist kynurenate (KYN) was replaced by glutamate during a synaptic response. Dose inhibition of the AMPA receptor EPSC by KYN was less than predicted by the equilibrium affinity of the antagonist, and the rise time of AMPA receptor miniature EPSCs (mEPSCs) was slowed by KYN. Both results indicated that KYN dissociated from AMPA receptors and was replaced by synaptically released transmitter. When transporters were blocked by D,L-threo-beta-hydroxyaspartic acid (THA) or Li+, the mEPSC rise time in the presence of KYN was slowed further, indicating that transporters affect the glutamate concentration in the first few hundred microseconds of the synaptic response. The glutamate transient necessary to cause these effects was determined by developing a detailed kinetic model of the AMPA receptor. The model replicated the effects of KYN on the amplitude and rise time of the synaptic responses when driven by glutamate transients that were similar to previous estimates (; ). The effects of THA were replicated by slowing and enlarging the slower phase of the dual component transient by about 20% or by prolonging the single component by almost 40%. Because transport is too slow to account for these effects, it is concluded that transporters buffer glutamate in the synaptic cleft.
TL;DR: Results indicate that both the temporal patterns of synaptic activity and the different temporal phases of synaptic enhancement are important in determining the neurotrophin dependence of plasticity in the hippocampus.
TL;DR: Direct communication between neurons and astrocytes via neurotransmitters could be a widespread form of communication in the brain which may affect many different aspects of brain function, such as glutamate uptake and the modulation of extracellular space.
TL;DR: It is reported that mice lacking Ras-GRF are impaired in the process of memory consolidation, as revealed by emotional conditioning tasks that require the function of the amygdala; learning and short-term memory are intact.
Abstract: Members of the Ras subfamily of small guanine-nucleotide-binding proteins are essential for controlling normal and malignant cell proliferation as well as cell differentiation. The neuronal-specific guanine-nucleotide-exchange factor, Ras-GRF/CDC25Mm, induces Ras signalling in response to Ca2+ influx and activation of G-protein-coupled receptors in vitro, suggesting that it plays a role in neurotransmission and plasticity in vivo. Here we report that mice lacking Ras-GRF are impaired in the process of memory consolidation, as revealed by emotional conditioning tasks that require the function of the amygdala; learning and short-term memory are intact. Electrophysiological measurements in the basolateral amygdala reveal that long-term plasticity is abnormal in mutant mice. In contrast, Ras-GRF mutants do not reveal major deficits in spatial learning tasks such as the Morris water maze, a test that requires hippocampal function. Consistent with apparently normal hippocampal functions, Ras-GRF mutants show normal NMDA (N-methyl-D-aspartate) receptor-dependent long-term potentiation in this structure. These results implicate Ras-GRF signalling via the Ras/MAP kinase pathway in synaptic events leading to formation of long-term memories.
TL;DR: It is reported that opioid inhibition of GABAergic synaptic currents in the PAG is controlled by a presynaptic voltage-dependent potassium conductance, and mechanisms account for the analgesic action of cyclooxygenase inhibitors in thePAG and their synergism with opioids.
Abstract: The midbrain region periaqueductal grey (PAG) is rich in opioid receptors and endogenous opioids and is a major target of analgesic action in the central nervous system. It has been proposed that the analgesic effect of opioids on the PAG works by suppressing the inhibitory influence of the neurotransmitter GABA (gamma-aminobutyric acid) on neurons that form part of a descending antinociceptive pathway. Opioids inhibit GABA-mediated (GABAergic) synaptic transmission in the PAG and other brain regions by reducing the probability of presynaptic neurotransmitter release, but the mechanisms involved remain uncertain. Here we report that opioid inhibition of GABAergic synaptic currents in the PAG is controlled by a presynaptic voltage-dependent potassium conductance. Opioid receptors of the mu type in GABAergic presynaptic terminals are specifically coupled to this potassium conductance by a pathway involving phospholipase A2, arachidonic acid and 12-lipoxygenase. Furthermore, opioid inhibition of GABAergic synaptic transmission is potentiated by inhibitors of the enzymes cyclooxygenase and 5-lipoxygenase, presumably because more arachidonic acid is available for conversion to 12-lipoxygenase products. These mechanisms account for the analgesic action of cyclooxygenase inhibitors in the PAG and their synergism with opioids.
TL;DR: It is reported that in cerebellar stellate cells, where variability in GABA miniature synaptic currents is particularly marked, the distribution of quantal amplitudes parallels that of synaptic GABA(A) receptor number, and it is shown that postsynaptic GABA( A) receptor density is uniform, allowing synaptic area to be used as a measure of relative receptor content.
01 Jan 1997
TL;DR: This chapter focuses on synaptically-gated currents of all kinds, including neuromodulators, which are readily modeled by Markov kinetics, which provide means to build coherent neural models in which subcellular, cellular, and network properties are described within the same formalism.
Abstract: The remarkably successful quantitative description of the action potential introduced by Hodgkin and Huxley (1952) is still widely used over 40 years since its introduction. The classical Hodgkin-Huxley description was not only accurate, it was also readily extensible to many other voltage-dependent currents. More recent single channel recording techniques (Sakmann and Neher, 1995) have been used to prove that voltage-dependent currents arise from populations of individual ion channels undergoing rapid transitions between conducting and non-conducting states. The macroscopic behavior of the currents can be accurately captured using kinetic models that describe the transitions between conformational states of these ion channels. This class of models, of which the Hodgkin-Huxley model is an instance, are commonly known as Markov models. Kinetic models not only provide good descriptions of voltage-dependent ionic currents but are general enough to describe almost all processes essential to neurophysiology. We will focus in this chapter on synaptically-gated currents of all kinds, including neuromodulators, which are readily modeled by Markov kinetics. Moreover, many important biochemical reactions, including second-messenger systems, synaptic release, and enzymatic cascades can also be described by kinetic schemes. As a consequence, kinetic models provide means to build coherent neural models in which subcellular, cellular, and network properties are described within the same formalism (see Destexhe et al., 1994c). Kinetic models are inherently exible in their level of detail, ranging from the most detailed and biophysically realistic gating models to highly simpli ed representations. Some detailed models determined from voltage-clamp studies have more than a dozen states (e.g.,
TL;DR: At crayfish neuromuscular junctions, several inhibitors of mitochondrial Ca2+ uptake and release blocked PTP and the persistence of presynaptic residual [Ca2+]i, while endoplasmic reticulum (ER) Ca2- pump inhibitors and release channel activators had no effects.
TL;DR: The notions of diffuse transmission and of an ambient level of ACh in the CNS could also be of clinical relevance, in accounting for the production and nature of certain cholinergic deficits and the efficacy of substitution therapies.
TL;DR: The effects of a potent and selective agonist and a selective antagonist are used to show that kainate receptors, comprised of or containing GluR5 subunits, regulate synaptic inhibition in the hippocampus, an action that could contribute to the epileptogenic effects of kainates.
Abstract: The principal excitatory neurotransmitter in the vertebrate central nervous system, L-glutamate, acts on three classes of ionotripic glutamate receptors, named after the agonists AMPA (α-amino-3-hydroxy-5-methyl-4-isoxalole-4-propionic acid), NMDA ( N -methyl-D-aspartate) and kainate1 The development of selective pharmacological agents has led to a detailed understanding ofthe physiological and pathological roles of AMPA and NMDA receptors2,3,4,5,6,7,8 In contrast, the lack of selective kainate receptor ligands has greatly hindered progress in understanding the rolesof kainate receptors9,10 Here we describe the effects of a potent and selective agonist, ATPA (( RS)-2-amino-3-(3-hydroxy-5- tert -butylisoxazol-4-yl)propanoic acid) and a selective antagonist, LY294486 ((3SR, 4aRS, 6SR, 8aRS)-6-((((1H-tetrazol-5-yl) methyl)oxy)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylic acid), of the GluR5 subtype of kainate receptor11 We have used these agents to show that kainate receptors, comprised of or containing GluR5 subunits, regulate synaptic inhibition in the hippocampus, an action that could contribute to the epileptogenic effects of kainate12,13,14,15,16,17
TL;DR: The results suggest that glutamate transporters play a critical role in limiting the extrasynaptic diffusion of glutamate, thereby minimizing cross-talk between neighboring excitatory synapses.
TL;DR: It is concluded that synaptic transmission of GABA and glutamate is strictly compartmentalized and as a result, these amino acids can hardly leak out of the synaptic cleft and reach the extracellular space where the dialysis probe samples.
Abstract: Microdialysis has become a frequently used method to study extracellular levels of GABA and glutamate in the central nervous system. However, the fact that the major part of GABA and glutamate as measured by microdialysis does not fulfill the classical criteria for exocytotic release questions the vesicular origin of the amino acids in dialysates. Glial metabolism or reversal of the (re)uptake sites has been suggested to be responsible for the pool of nonexocytotically released amino-acid transmitters that seem to predominate over the neuronal exocytotic pool. The origin of extracellular GABA and glutamate levels and, as a consequence, the implications of changes in these levels upon manipulations are therefore obscure. This review critically analyzes what microdialysis data signify, i.e., whether amino-acid neurotransmitters sampled by microdialysis represent synaptic release, carrier-mediated release, or glial metabolism. The basal levels of GABA and glutamate are virtually tetrodotoxin- and calcium-independent. Given the fact that evidence for nonexocytotic release mediated by reversal of the uptake sites as a release mechanism relevant for normal neurotransmission is so far limited to conditions of "excessive stimulation," basal levels most likely reflect a nonneuronal pool of amino acids. Extracellular GABA and glutamate concentrations can be enhanced by a wide variety of pharmacological and physiological manipulations. However, it is presently impossible to ascertain that the stimulated GABA and glutamate in dialysates are of neuronal origin. On the other hand, under certain stimulatory conditions, increases in amino-acid transmitters can be obtained in the presence of tetrodotoxin, again suggesting that aspecific factors not directly related to neurotransmission underlie these changes in extracellular levels. It is concluded that synaptic transmission of GABA and glutamate is strictly compartmentalized and as a result, these amino acids can hardly leak out of the synaptic cleft and reach the extracellular space where the dialysis probe samples.
TL;DR: The hypothesis that NO plays an important role in synaptic transmission is supported and some but not all previously contradictory results are explained.