Metabotropic glutamate receptors in the trafficking of ionotropic glutamate and GABA(A) receptors at central synapses

The trafficking of ionotropic glutamate (AMPA, NMDA and kainate) and GABA(A) receptors in and out of, or laterally along, the postsynaptic membrane has recently emerged as an important mechanism in the regulation of synaptic function, both under physiological and pathological conditions, such as information processing, learning and memory formation, neuronal development, and neurodegenerative diseases. Non-ionotropic glutamate receptors, primarily group I metabotropic glutamate receptors (mGluRs), co-exist with the postsynaptic ionotropic glutamate and GABA(A) receptors. The ability of mGluRs to regulate postsynaptic phosphorylation and Ca(2+) concentration, as well as their interactions with postsynaptic scaffolding/signaling proteins, makes them well suited to influence the trafficking of ionotropic glutamate and GABA(A) receptors. Recent studies have provided insights into how mGluRs may impose such an influence at central synapses, and thus how they may affect synaptic signaling and the maintenance of long-term synaptic plasticity. In this review we will discuss some of the recent progress in this area: i) long-term synaptic plasticity and the involvement of mGluRs; ii) ionotropic glutamate receptor trafficking and long-term synaptic plasticity; iii) the involvement of postsynaptic group I mGluRs in regulating ionotropic glutamate receptor trafficking; iv) involvement of postsynaptic group I mGluRs in regulating GABA(A) receptor trafficking; v) and the trafficking of postsynaptic group I mGluRs themselves.     

"Presynaptic silence" may be golden

Conversion of "silent" synapses into active ones is a likely mechanism for long-term potentiation (LTP), an experimental paradigm for studying information storage. A widely accepted mechanism that has been suggested for synaptic silence is that functional AMPA glutamate receptors (AMPARs) are absent on the subsynaptic membrane. Evidence is presented here that in many cases the cause of apparent "silence" is presynaptic and due to a low level of glutamate release. Increased transmitter release is crucial for early LTP maintenance. Delayed modifications in postsynaptic receptors matched with transmitter release changes underlie structural alterations associated with late LTP phases.     

Cocaine-induced metaplasticity in the nucleus accumbens: silent synapse and beyond

The neuroadaptation theory of addiction suggests that, similar to the development of most memories, exposure to drugs of abuse induces adaptive molecular and cellular changes in the brain which likely mediate addiction-related memories or the addictive state. Compared to other types of memories, addiction-related memories develop fast and last extremely long, suggesting that the cellular and molecular processes that mediate addiction-related memories are exceptionally adept and efficient. We recently demonstrated that repeated exposure to cocaine generated a large portion of “silent” glutamatergic synapses within the nucleus accumbens (NAc). Silent glutamatergic synapses are synaptic connections in which only N-methyl-d-aspartic acid receptor (NMDAR)-mediated responses are readily detected whereas alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are absent or highly labile. Extensive experimental evidence suggests that silent synapses are conspicuously efficient plasticity sites at which long-lasting plastic changes can be more easily induced and maintained. Thus, generation of silent synapses can be regarded as a process of metaplasticity, which primes the NAc for subsequent durable and robust plasticity for addiction-related memories. Focusing on silent synapse-based metaplasticity, this review discusses how key brain regions, such as the NAc, utilize the metaplasticity mechanism to optimize the plasticity machineries to achieve fast and durable plastic changes following exposure to cocaine. A summary of recent related results suggests that upon cocaine exposure, newly generated silent synapses may prime excitatory synapses within the NAc for long-term potentiation (LTP), thus setting the direction of future plasticity. Furthermore, because cocaine-generated silent synapses are enriched in NMDARs containing the NR2B subunit, the enhanced NR2B-signaling may set up a selective recruitment of certain types of AMPARs. Thus, silent synapse-based metaplasticity may lead to not only quantitative but also qualitative alterations in excitatory synapses within the NAc. This review is one of the first systematic analyses regarding the hypothesis that drugs of abuse induce metaplasticity, which regulates the susceptibility, the direction, and the molecular details of subsequent plastic changes. Taken together, metaplasticity ultimately serves as a key step in mediating cascades of addiction-related plastic alterations.This article is part of a Special Issue entitled ‘Synaptic Plasticity and Addiction’.     

Input-specific plasticity at excitatory synapses mediated by endocannabinoids in the dentate gyrus

Endocannabinoids (eCBs) mediate transient and long-lasting synaptic plasticity in several brain structures. In the dentate gyrus, activation of the type 1 cannabinoid receptor (CB1R) by exogenous ligands reportedly depresses excitatory synaptic transmission. However, direct evidence of eCB signaling at excitatory synapses in this region has been lacking. Here, we demonstrate that eCB release can be induced by a brief postsynaptic depolarization of dentate granule cells (DGCs), which potently and transiently suppresses glutamatergic inputs from mossy cell interneurons (MCs) but not from entorhinal cortex via the lateral and medial perforant paths. This input-specific depolarization-induced suppression of excitation (DSE) is calcium-dependent and can be modulated by agonists of cholinergic and group I metabotropic glutamate receptors. Inhibiting the synthesis of 2-arachidonoyl glycerol (2-AG), one of the most abundant eCBs in the brain, by diacyglycerol lipase (DGL) does not abolish DSE. Moreover, preventing the breakdown of anandamide, the other main eCB, does not potentiate DSE. Thus, eCB signaling underlying DSE in the dentate does not require DGL activity and is unlikely to be mediated by anandamide. Finally, we find that manipulations known to induce eCB-LTD at other central synapses do not trigger LTD at MCF-DGC synapses.     

Activity-driven postsynaptic translocation of CaMKII

Ca2+ influx through the NMDA receptor and subsequent activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) are crucial for learning and one of its physiological correlates, long-term potentiation (LTP). Ca2+/calmodulin promotes CaMKII binding to several postsynaptic proteins, including the NMDA receptor. These interactions strategically place CaMKII at locations where Ca2+ influx through the NMDA receptor is highest for further activation of CaMKII and for phosphorylation of nearby AMPA receptors and of other proteins that are important for LTP. Ca2+-dependent postsynaptic CaMKII clustering is of specific interest because LTP is synapse specific: only synapses that experience LTP-inducing high-frequency activity exhibit LTP. Ca2+-driven protein binding ensures that CaMKII accumulates only at those synapses undergoing LTP. This selectivity is economical and could contribute to the synapse specificity of LTP because downstream effects of CaMKII will occur mainly at synapses that accumulate CaMKII. In this article, we provide an overview of recent progress in postsynaptic CaMKII anchoring and discuss its implication in synaptic plasticity and the etiology and potential treatments of neurological diseases.     

GABA_B受体的最新进展:从药理学到分子生物学(英文)

Bicuculline-insensitive receptors for the inhibitory neurotransmitter γ-aminobutyric acid (GABA), GABAB receptors, are a distinct subclass of receptors that mediate depression of synaptic transmission and contribute to neu-ronal inhibition. When activated, these receptors reduce transmission at excitatory and inhibitory synapses, as a result of an increase in K conductance, or a decrease in voltage-dependent Ca2 currents. They are also linked to G-proteins, or intracellular effector systems in a very complex manner. The recent development of highly specific and potent agonists and antagonists for these receptors has led to a much better understanding of their physiology and pharmacology, including their heterogeneity, as well as their molecular biology. Over the past year, expression and cloning studies have contributed to major advances in characterizing GABAB receptor structure, with the discovery of the amino acid sequences of GABABRla/R1b splice variants and GABABR2 receptors. These isoforms are     

Voluntary Exercise and Sucrose Consumption Enhance Cannabinoid CB1 Receptor Sensitivity in the Striatum

The endogenous cannabinoid system is involved in the regulation of the central reward pathway. Running wheel and sucrose consumption have rewarding and reinforcing properties in rodents, and share many neurochemical and behavioral characteristics with drug addiction. In this study, we investigated whether running wheel or sucrose consumption altered the sensitivity of striatal synapses to the activation of cannabinoid CB1 receptors. We found that cannabinoid CB1 receptor-mediated presynaptic control of striatal inhibitory postsynaptic currents was remarkably potentiated after these environmental manipulations. In contrast, the sensitivity of glutamate synapses to CB1 receptor stimulation was unaltered, as well as that of GABA synapses to the stimulation of presynaptic GABAB receptors. The sensitization of cannabinoid CB1 receptor-mediated responses was slowly reversible after the discontinuation of running wheel or sucrose consumption, and was also detectable following the mobilization of endocannabinoids by metabotropic glutamate receptor 5 stimulation. Finally, we found that the upregulation of cannabinoid transmission induced by wheel running or sucrose had a crucial role in the protective effects of these environmental manipulations against the motor and synaptic consequences of stress.     

Dopaminergic signaling in dendritic spines

Dopamine regulates movement, motivation, reward, and learning and is implicated in numerous neuropsychiatric and neurological disorders. The action of dopamine is mediated by a family of seven-transmembrane G protein-coupled receptors encoded by at least five dopamine receptor genes (D1, D2, D3, D4, and D5), some of which are major molecular targets for diverse neuropsychiatric medications. Dopamine receptors are present throughout the soma and dendrites of the neuron, but accumulating ultrastructural and biochemical evidence indicates that they are concentrated in dendritic spines, where most of the glutamatergic synapses are established. By modulating local channels, receptors, and signaling modules in spines, this unique population of postsynaptic receptors is strategically positioned to control the excitability and synaptic properties of spines and mediate both the tonic and phasic aspects of dopaminergic signaling with remarkable precision and versatility. The molecular mechanisms that underlie the trafficking, targeting, anchorage, and signaling of dopamine receptors in spines are, however, largely unknown. The present commentary focuses on this important subpopulation of postsynaptic dopamine receptors with emphases on recent molecular, biochemical, pharmacological, ultrastructural, and physiological studies that provide new insights about their regulatory mechanisms and unique roles in dopamine signaling.     

Presynaptic mechanisms involved in the expression of STP and LTP at CA1 synapses in the hippocampus

The study of long-term potentiation (LTP) has for many years been the centre of a raging debate as to whether the process is expressed by presynaptic or postsynaptic mechanisms. Here we present evidence that two forms of synaptic plasticity at CA3-CA1 synapses in the hippocampus are expressed by presynaptic changes. One form is short-term potentiation (STP) and the other a neonatal form of early-LTP (E-LTP). We review recent experimental data that suggests that this latter form of LTP involves an increase in the probability of neurotransmitter release (Pr). We describe how this is caused by the rapid down-regulation of a high affinity kainate receptor, which otherwise responds to ambient levels of l-glutamate by depressing Pr.     

Distinct roles of group I mGlu receptors in striatal function

In the recent past, evidence accumulated in favour of a central role of group I metabotropic glutamate (mGlu) receptors, mGlu1 and mGlu5, in the modulation of cell excitability both of striatal medium spiny projection neurons (MSNs) and interneuronal population. Electrophysiological and pharmacological studies have clearly shown that activation of mGlu1 and mGlu5 receptors exerts distinct actions, depending on the neuronal subtype involved. MGlu5 receptor activation mediates the potentiation of NMDA responses in MSNs, and underlies the retrograde inhibitory signaling by endocannabinoids at corticostriatal synapses. Conversely, both group I mGlu receptors are involved in long-term synaptic plasticity of MSNs. Likewise, either mGlu1 or mGlu5 receptors are engaged in shaping the excitability of large cholinergic interneurons, playing different roles in the membrane responses. Differently, although GABAergic parvalbumin-positive, fast-spiking interneurons have been shown to express both group I receptors, only mGlu1 receptor seems to mediate membrane and synaptic responses. This review provides a brief survey of the cellular and synaptic actions of group I mGlu receptors, and discusses the potential relevance of these findings in neostriatal function and motor control.     

Opioid receptor regulation of muscarinic acetylcholine receptor-mediated synaptic responses in the hippocampus

A common feature of many synapses is their regulation by neurotransmitters other than those released from the presynaptic terminal. This aspect of synaptic transmission is often mediated by activation of G protein coupled receptors (GPCRs) and has been most extensively studied at amino acid-mediated synapses where ligand gated receptors mediate the postsynaptic signal. Here we have investigated how opioid receptors modulate synaptic transmission mediated by muscarinic acetylcholine receptors (mAChRs) in hippocampal CA1 pyramidal neurones. Using a cocktail of glutamate and gamma-amino-butyric acid (GABA) receptor antagonists a slow pirenzepine-sensitive excitatory postsynaptic potential (EPSP(M)) that was associated with a small increase in cell input resistance could be evoked in isolation. This response was enhanced by the acetylcholine (ACh) esterase inhibitor physostigmine (1 microM) and depressed by the vesicular ACh transport inhibitor vesamicol (50 microM). The mu-opioid receptor agonists DAMGO (1-5 microM) and etonitazene (100 nM), but not the delta- and kappa-opioid receptor selective agonists DTLET (1 microM) and U-50488 (1 microM), potentiated this EPSP(M) (up to 327%) without affecting cell membrane potential or input resistance; an effect that was totally reversed by naloxone (5 microM). In contrast, postsynaptic depolarizations and increases in cell input resistance evoked by carbachol (3 microM) were unaffected by DAMGO (1-5 microM) but were abolished by atropine (1 microM). Taken together these data provide good evidence for a mu-opioid receptor-mediated presynaptic enhancement of mAChR-mediated EPSPs in hippocampal CA1 pyramidal neurones.     

Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia

Several lines of evidence implicate NMDA receptor dysfunction in the cognitive deficits of schizophrenia, suggesting that pharmacological manipulation of the NMDA receptor may be a feasible therapeutic strategy for treatment of these symptoms. Although direct manipulation of regulatory sites on the NMDA receptor is the most obvious approach for pharmacological intervention, targeting the G-protein coupled metabotropic glutamate (mGlu) receptors may be a more practical strategy for long-term regulation of abnormal glutamate neurotransmission. Heterogeneous distribution, both at structural and synaptic levels, of at least eight subtypes of mGlu receptors suggests that selective pharmacological manipulation of these receptors may modulate glutamatergic neurotransmission in a regionally and functionally distinct manner. Two promising targets for improving cognitive functions are mGlu5 or mGluR2/3 receptors, which can modulate the NMDA receptor-mediated signal transduction by pre- or postsynaptic mechanisms. Preclinical studies indicate that activation of these subtypes of mGlu receptors may be an effective strategy for reversing cognitive deficits resulting form reduced NMDA receptor mediated neurotransmission.     

Long-term potentiation persists in an occult state following mGluR-dependent depotentiation

Depotentiation, the reversal of long-term potentiation (LTP), can be induced by activation of metabotropic glutamate receptors (mGluRs) or NMDA receptors (NMDARs). Although NMDAR-dependent depotentiation is due to a protein phosphatase-dependent erasure of LTP, the notion that mGluR-dependent depotentiation also involves LTP erasure is controversial. To address this issue we used electrophysiological and biochemical approaches to investigate mGluR-dependent depotentiation in hippocampal slices. Activating group I mGluRs with (R,S)-3,5-dihydroxyphenylglycine (DHPG) induced robust depotentiation in both the CA1 and CA3 regions of hippocampal slices. Western immunoblotting of samples prepared from DHPG-treated slices revealed, however, that activation of group I mGluRs causes a transient increase in phosphorylation of AMPA receptor GluR1 subunits at sites crucial for LTP and under some conditions causes persistent activation of alphaCamKII. The paradoxical ability of DHPG to induce depotentiation while at the same time activating signaling pathways involved in LTP suggests that LTP might not be erased by mGluR-dependent depotentiation. Consistent with this, DHPG-induced depotentiation did not restore the ability of high-frequency stimulation to induce LTP at synapses that had previously undergone saturating levels of LTP. In addition, blocking the expression of DHPG-induced LTD revealed hidden LTP at depotentiated synapses. Our results indicate that LTP and mGluR-dependent LTD can co-exist at excitatory synapses.     

Thiamethoxam, a poor agonist of nicotinic acetylcholine receptors expressed on isolated cell bodies, acts as a full agonist at cockroach cercal afferent/giant interneuron synapses

Thiamethoxam (TMX) is a second-generation neonicotinoid which is known to induce toxic effects on insects and mammalians. Recently, it has been proposed that TMX is a poor agonist of insect nicotinic acetylcholine receptors (nAChRs) on isolated cell bodies. Here, we have studied its effect on synaptic transmission. Our results demonstrate that TMX acts as an agonist of nAChRs expressed on cockroach cercal afferent giant/interneuron synapses as bath applications of TMX induce a strong reversible depolarization of the sixth abdominal ganglion. This response was reduced by the nicotinic antagonists mecamylamine and methyllicaconitine, but was insensitive to d-tubocurarine. Interestingly, TMX-induced depolarization was partially reduced by the muscarinic antagonist atropine, suggesting that TMX could bind to a ‘mixed nicotinic/muscarinic’ receptor.Compared to previous studies, we proposed that TMX is able to act as agonist of insect nAChRs expressed at cercal afferent/giant interneuron synapses. Moreover, our results suggest that nAChRs expressed on synaptic ganglion are distinct to nAChRs expressed on isolated cell bodies and that synaptic receptors have higher affinity to TMX resulting to a depolarization of postsynaptic nicotinic receptors.     

The excitatory postsynaptic density is a size exclusion diffusion environment

Receptors are concentrated in the postsynaptic membrane but can enter and exit synapses rapidly during both basal turnover and processes of synaptic plasticity. How the exchange of receptors by lateral diffusion between synaptic and extrasynaptic areas is regulated remains largely unknown. We investigated the structural properties of the postsynaptic membrane that allow these movements by addressing the diffusion behaviors of AMPA receptors (AMPARs) and different lipids. Using single molecule tracking we found that not only AMPARs but also lipids, which are not synaptically enriched, display confined diffusion at synapses. Each molecule type displays a different average confinement area, smaller molecules being confined to smaller areas. Glutamate application increases the mobility of all molecules. The structure of the synaptic membrane is thus probably organized as a size exclusion matrix and this controls the rate of exchange of molecules with the extrasynaptic membrane.     

Therapeutic applications of benzodiazepine receptor ligands in anxiety

In this short review, evidence is presented to show that the benzodiazepines produce their variety of pharmacological effects by activating specific receptors that form part of the main inhibitory neurotransmitter receptor system, the γ‐amino‐butyric acid (GABA) system, in the mammalian brain. Different classes of benzodiazepine receptor ligands have been developed which can alleviate anxiety or produce anxiety according to the fine structural changes that occur when the ligands interact with the benzodiazepine receptor. There is some evidence that endogenous substances in the brain can cause either an increase or a reduction in the anxiety state by acting on the benzodiazepine receptor. The unique nature of the benzodiazepine receptor, and the disparate properties of the drugs that act on this receptor, should allow plenty of scope for the development of novel compounds with selective anxiolytic and other properties in the future. Lastly, despite the evidence from animal studies that benzodiazepine receptor function changes in response to drug treatment, there is little evidence from human brain studies that such changes are relevant to the phenomena of tolerance, dependence and withdrawal effects that have been the recent cause for public concern. Copyright © 1999 John Wiley & Sons, Ltd.     

Glutamate in the enteric nervous system

Several lines of evidence indicate a role for glutamate in the regulation of gut motility and secretion; however, the receptor subtypes that mediate the effects of this amino acid are still incompletely understood. There has, however, been recent progress in pharmacological characterization of enteric glutamate receptor subtypes. In the past two years, investigators have demonstrated that in addition to ionotropic glutamate receptors, the enteric nervous system contains functional group I metabotropic glutamate receptors that appear to participate in enteric reflexes. This opens up an entirely new arena in which to study the roles of glutamate in gut function and presents potential new target sites for drug development.     

Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE)

Depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE) are two related forms of short-term synaptic plasticity of GABAergic and glutamatergic transmission, respectively. They are induced by calcium concentration increases in postsynaptic cells and are mediated by the release of a retrograde messenger, which reversibly inhibits afferent synapses via presynaptic mechanisms.We review here: 1. The evidence accumulated during the 1990s that has led to the conclusion that DSI/DSE rely on retrograde signaling. 2. The more recent research that has led to the identification of endocannabinoids as the retrograde messengers responsible for DSI/DSE. 3. The possible mechanisms by which presynaptic type 1 cannabinoid receptors reduce synaptic efficacy during DSI/DSE. 4. The possible modes of induction of DSI/DSE by physiological activity patterns, and the partially conflicting evaluations of the calcium concentration increases required for cannabinoid synthesis. 5. Finally, the relation between DSI/DSE and other forms of long- and short-term synaptic inhibition, which were more recently associated with the production of endocannabinoids by postsynaptic cells. We conclude that recent studies on DSI/DSE have uncovered a specific and original mode of action for endocannabinoids in the brain, and that they have opened new avenues to understand the role of retrograde signaling in central synapses.