NMDA Receptor-independent Long-term Potentiation Research Articles

NMDA receptor-independent LTP in mammalian nervous system.

Long-term potentiation (LTP) of synaptic transmission is a form of activity-dependent synaptic plasticity that exists at most synapses in the nervous system. In the central nervous system (CNS), LTP has been recorded at numerous synapses and is a prime candidate mechanism associating activity-dependent plasticity with learning and memory. LTP involves long-lasting increase in synaptic strength with various underlying mechanisms. In the CNS, the predominant type of LTP is believed to be dependent on activation of the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR), which is highly calcium-permeable. However, various forms of NMDAR-independent LTP have been identified in diverse areas of the nervous system. The NMDAR-independent LTP may require activation of glutamate metabotropic receptors (mGluR) or ionotropic receptors other than NMDAR such as nicotinic acetylcholine receptor (α7-nAChR), serotonin 5-HT3 receptor or calcium-permeable AMPA receptor (CP-AMPAR). In this review, NMDAR-independent LTP of various areas of the central and peripheral nervous systems are discussed.

Nicotinic receptor activation induces NMDA receptor independent long-term potentiation of glutamatergic signalling in hippocampal oriens interneurons.

Key points Long‐term potentiation of glutamatergic transmission to hippocampal interneurons in stratum oriens does not require NMDA receptors and the induction mechanisms are incompletely understood.Extracellular stimulation, conventionally used to monitor synaptic strength and induce long‐term potentiation (LTP), does not exclusively recruit glutamatergic axons.We used optogenetic stimulation of either glutamatergic or cholinergic afferents to probe the relative roles of different signalling mechanisms in LTP induction.Selective stimulation of cholinergic axons was sufficient to induce LTP, which was prevented by chelating postsynaptic Ca2+ or blocking nicotinic receptors.The present study adds nicotinic receptors to the list of sources of Ca2+ that induce NMDA receptor independent LTP in hippocampal oriens interneurons. Many interneurons located in stratum oriens of the rodent hippocampus exhibit a form of long‐term potentiation (LTP) of glutamatergic transmission that does not depend on NMDA receptors for its induction but, instead, requires Ca2+‐permeable AMPA receptors and group I metabotropic glutamate receptors. A role for cholinergic signalling has also been reported. However, electrical stimulation of presynaptic axons, conventionally used to evoke synaptic responses, does not allow the relative roles of glutamatergic and cholinergic synapses in the induction of LTP to be distinguished. Here, we show that repetitive optogenetic stimulation confined to cholinergic axons is sufficient to trigger a lasting potentiation of glutamatergic signalling. This phenomenon shows partial occlusion with LTP induced by electrical stimulation, and is sensitive to postsynaptic Ca2+ chelation and blockers of nicotinic receptors. ACh release from cholinergic axons is thus sufficient to trigger heterosynaptic potentiation of glutamatergic signalling to oriens interneurons in the hippocampus.

A new mouse line with reduced GluA2 Q/R site RNA editing exhibits loss of dendritic spines, hippocampal CA1-neuron loss, learning and memory impairments and NMDA receptor-independent seizure vulnerability

Calcium (Ca2+)-permeable AMPA receptors may, in certain circumstances, contribute to normal synaptic plasticity or to neurodegeneration. AMPA receptors are Ca2+-permeable if they lack the GluA2 subunit or if GluA2 is unedited at a single nucleic acid, known as the Q/R site. In this study, we examined mice engineered with a point mutation in the intronic editing complementary sequence (ECS) of the GluA2 gene, Gria2. Mice heterozygous for the ECS mutation (named GluA2+/ECS(G)) had a ~ 20% reduction in GluA2 RNA editing at the Q/R site. We conducted an initial phenotypic analysis of these mice, finding altered current-voltage relations (confirming expression of Ca2+-permeable AMPA receptors at the synapse). Anatomically, we observed a loss of hippocampal CA1 neurons, altered dendritic morphology and reductions in CA1 pyramidal cell spine density. Behaviourally, GluA2+/ECS(G) mice exhibited reduced motor coordination, and learning and memory impairments. Notably, the mice also exhibited both NMDA receptor-independent long-term potentiation (LTP) and vulnerability to NMDA receptor-independent seizures. These NMDA receptor-independent seizures were rescued by the Ca2+-permeable AMPA receptor antagonist IEM-1460. In summary, unedited GluA2(Q) may have the potential to drive NMDA receptor-independent processes in brain function and disease. Our study provides an initial characterisation of a new mouse model for studying the role of unedited GluA2(Q) in synaptic and dendritic spine plasticity in disorders where unedited GluA2(Q), synapse loss, neurodegeneration, behavioural impairments and/or seizures are observed, such as ischemia, seizures and epilepsy, Huntington’s disease, amyotrophic lateral sclerosis, astrocytoma, cocaine seeking behaviour and Alzheimer’s disease.

T-type calcium channels contribute to NMDA receptor independent synaptic plasticity in hippocampal regular-spiking oriens-alveus interneurons.

Key points Regular‐spiking interneurons in the hippocampal stratum oriens exhibit a form of long‐term potentiation of excitatory transmission that is independent of NMDA receptors but requires co‐activation of Ca2+‐permeable AMPA receptors and group I metabotropic glutamate receptors.We show that T‐type Ca2+ channels are present in such interneurons.Blockade of T‐type currents prevents the induction of long‐term potentiation, and also interferes with long‐lasting potentiation induced either by postsynaptic trains of action potentials or by pairing postsynaptic hyperpolarization with activation of group I metabotropic receptors.Several Ca2+ sources thus converge on the induction of NMDA receptor independent synaptic plasticity. NMDA receptor independent long‐term potentiation (LTP) in hippocampal stratum oriens‐alveus (O/A) interneurons requires co‐activation of postsynaptic group I metabotropic glutamate receptors (mGluRs) and Ca2+‐permeable AMPA receptors. The rectification properties of such AMPA receptors contribute to the preferential induction of LTP at hyperpolarized potentials. A persistent increase in excitatory transmission can also be triggered by exogenous activation of group I mGluRs at the same time as the interneuron is hyperpolarized, or by postsynaptic trains of action potentials in the absence of presynaptic stimulation. In the present study, we identify low‐threshold transient (T‐type) channels as a further source of Ca2+ that contributes to synaptic plasticity. T‐type Ca2+ currents were detected in mouse regular‐spiking O/A interneurons. Blocking T‐type currents pharmacologically prevented LTP induced by high‐frequency stimulation of glutamatergic axons, or by application of the group I mGluR agonist dihydroxyphenylglycine, paired with postsynaptic hyperpolarization. T‐type current blockade also prevented synaptic potentiation induced by postsynaptic action potential trains. Several sources of Ca2+ thus converge on NMDA receptor independent LTP induction in O/A interneurons.

Induction of Anti-Hebbian LTP in CA1 Stratum Oriens Interneurons: Interactions between Group I Metabotropic Glutamate Receptors and M1 Muscarinic Receptors.

In the hippocampus, a form of NMDA receptor-independent long-term potentiation (LTP) occurs at excitatory synapses made on some inhibitory neurons. This is preferentially induced when postsynaptic interneurons are hyperpolarized, depends on Ca(2+) entry through Ca(2+)-permeable AMPA receptors, and has been labeled anti-Hebbian LTP. Here we show that this form of LTP also depends on activation of both group I mGluR and M1 mAChRs. We demonstrate that these G-protein coupled receptors (GPCRs) interact, because the blockade of one receptor suppresses long-term effects of activation of the other GPCR on both LTP and interneuron membrane potential. This LTP was also detected in paired recordings, although only when both presynaptic and postsynaptic recordings did not perturb the intracellular medium. Changes in EPSP amplitude distributions in dual recordings were consistent with a presynaptic locus of expression.

Long-term potentiation in hilar circuitry modulates gating by the dentate gyrus.

The dentate gyrus serves as a gateway to the hippocampus, filtering and processing sensory inputs as an animal explores its environment. The hilus occupies a strategic position within the dentate gyrus from which it can play a pivotal role in these functions. Inputs from dentate granule cells converge on the hilus, and excitatory hilar mossy cells redistribute these signals back to granule cells to transform a pattern of cortical input into a new pattern of output to the hippocampal CA3 region. Using voltage-sensitive dye to image electrical activity in rat hippocampal slices, we explored how long-term potentiation (LTP) of different excitatory synapses modifies the flow of information. Theta burst stimulation of the perforant path potentiated responses throughout the molecular layer, but left responses in the CA3 region unchanged. By contrast, theta burst stimulation of the granule cell layer potentiated responses throughout the molecular layer, as well as in the CA3 region. Theta burst stimulation of the granule cell layer potentiated CA3 responses not only to granule cell layer stimulation but also to perforant path stimulation. Potentiation of responses in the CA3 region reflected NMDA receptor-dependent LTP of upstream synapses between granule cells and mossy cells, with no detectable contribution from NMDA receptor-independent LTP of local CA3 mossy fiber synapses. Potentiation of transmission to the CA3 region required LTP in both granule cell→mossy cell and mossy cell→granule cell synapses. This bidirectional plasticity enables hilar circuitry to regulate the flow of information through the dentate gyrus and on to the hippocampus.

Involvement of NO in NMDA receptor-independent long-term potentiation

Long-term potentiation (LTP) is a persistent increase in synaptic efficacy and, throughout the brain, a putative model of processes underlying learning and memory. Multiple forms of LTP exist with different dependences on NMDA receptor activation. Since nNOS is thought to be preferentially activated by NMDA receptor channel-opening, the role of NO in NMDA receptor-dependent LTP has attracted much attention. In contrast, less is known about the contribution of NO to NMDA receptor-independent LTP. At hippocampal CA3–CA1 synapses, a component of 200 Hz stimulation-induced LTP is resistant to NMDA receptor antagonism but reduced by L-type voltage-gated Ca 2+ channel (L-VGCC) inhibition. Since this component (called here L-VGCC-dependent LTP) shares properties with NO-dependent LTP, we tested the involvement of NO in it. Using field potential recording in hippocampal slices pre-incubated with the NMDA antagonist, D-AP5 (100 μM), we found that the L-VGCC-dependent LTP could be inhibited by NOS antagonism (100 μM L-NNA). The time-course of the inhibition was similar to the reduction caused by the L-VGCC inhibitor, nifedipine (30 μM), and could be mimicked by the NO-targeted guanylyl cyclase antagonist, ODQ (10 μM), suggesting that the NO signal involved was transduced by cGMP. The results of experiments on slices from eNOS-deficient mice, together with the lack of iNOS in hippocampal slices, suggested that nNOS was the sole source of the NO required. These data extend an essential role for neuron-derived NO from NMDA receptor-dependent to NMDA receptor-independent LTP and suggest that some forms of LTP necessitate a currently unknown mechanism for nNOS activation.

Group I mGluR Agonist-Evoked Long-Term Potentiation in Hippocampal Oriens Interneurons

Several subtypes of interneurons in the feedback circuit in stratum oriens of the hippocampus exhibit NMDA receptor-independent long-term potentiation (LTP) at glutamatergic synapses made by local pyramidal neurons. LTP has been reported with both "Hebbian" and "anti-Hebbian" induction protocols, where high-frequency presynaptic stimulation is paired with either postsynaptic depolarization or hyperpolarization. Do these phenomena represent distinct forms of plasticity, dependent on group I metabotropic receptors (mGluRs) and rectifying Ca2+ -permeable AMPA receptors, respectively? Blockade of either mGluR1 or mGluR5 prevented anti-Hebbian LTP induction in stratum oriens interneurons in rat hippocampal slices. Exogenous activation of group I mGluRs by the selective agonist (S)-3,5-dihydroxyphenylglycine (DHPG) was unable to induce LTP on its own, and instead depressed excitatory transmission. However, when paired with postsynaptic hyperpolarization, DHPG or the group I metabotropic receptor (mGluR5)-selective agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG) elicited a delayed long-lasting potentiation, which was accompanied by a decrease in paired-pulse facilitation. Anti-Hebbian LTP occluded the effect of DHPG paired with hyperpolarization, implying that the induction cascades triggered by both conjunctions of stimuli converge on common expression mechanisms.

Copper Inhibits NMDA Receptor‐Independent LTP and Modulates the Paired‐Pulse Ratio after LTP in Mouse Hippocampal Slices

Copper misregulation has been implicated in the pathological processes underlying deterioration of learning and memory in Alzheimer's disease and other neurodegenerative disorders. Supporting this, inhibition of long-term potentiation (LTP) by copper (II) has been well established, but the exact mechanism is poorly characterized. It is thought that an interaction between copper and postsynaptic NMDA receptors is a major part of the mechanism; however, in this study, we found that copper (II) inhibited NMDA receptor-independent LTP in the CA3 region of hippocampal slices. In addition, in the CA3 and CA1 regions, copper modulated the paired-pulse ratio (PPR) in an LTP-dependent manner. Combined, this suggests the involvement of a presynaptic mechanism in the modulation of synaptic plasticity by copper. Inhibition of the copper-dependent changes in the PPR with cyclothiazide suggested that this may involve an interaction with the presynaptic AMPA receptors that regulate neurotransmitter release.

Copper Status in Alzheimer's Disease and Other Neurodegenerative Disorders: Genetics, Mechanisms, Neurophysiology, and Therapies

The present special issue is an attempt to explore some of the diverse aspects of copper involvement in the physiology of the brain. The contributions examine very hot topics, such as the relationship between copper and synaptic transmission or copper involvement in Alzheimer's disease (AD) and even include a computational model of copper binding to the amyloid precursor protein (S. Azini and R. Rouk 2011). In this model, the authors applied theoretical methods of computational chemistry to determine structure, binding affinities, and reduction potentials of Cu(II) and Cu(I) bound to models of the Asp1, Ala2, His6, and His13His14 regions of the amyloid beta peptide. A bulk of new studies has been recently published on the role of copper in the biological processes subtending synaptic transmission, and three contributions on this subject are included in the special issue. Specifically, one contribution describes a study in a cellular model of oocytes, which investigated the connection between copper and the prion protein in neurotransmission mediated by ATP-evoked currents (R. A. Lorca et al., 2011). A study on mouse hippocampal slices investigates copper inhibition of glutamatergic NMDA receptor-independent long-term potentiation (N. L. Salazar-Weber and J. P. Smith 2011), and a human model explores the effects of systemic copper on glutamatergic mediated excitability in the primary somatosensory cortex (F. Tecchio et al., 2011). Since the original papers that have been fuelling a heated debate in the literature about the pros and cons of copper on cognition are rather scattered and discordant, the aim of the editors was to select contributions that all together would provide the reader with an adequate overview of the issue but would still leave the reader free to form personal and hopefully critical opinions. In this section, some of the papers give a good overview of the nonunivocal in vitro, animal and human findings which demonstrate the involvement of copper in AD (D. Kaden et al. 2011). Also, in their paper, Y. Manso and colleagues (Y. Manso et al., 2011) review the preclinical and clinical literature dedicated to therapeutic interventions aimed at delaying or possibly reverting AD progression via the modulation of brain copper levels (Y. Manso et al., 2011). In the same section, some reports are preliminary but still original in their content, as, for example, the paper dealing with the influence of water quality on the cholesterol-fed rabbit model, which suggests that the origin of the brain neurofibrillary tangles is possibly systemic and somehow related to disturbances to the blood brain barrier mediated by copper ingested through the diet (D. L. Sparks et al., 2011), as well as the study by S. Bucossi and coworkers (S. Bucossi et al., 2011) which demonstrates an association between single nucleotide polymorphisms of the Wilson's disease gene and AD. T. U. Hoogenraad discusses further the link between these two neurological disorders (T. U. Hoogenraad 2011), which share the presence of abnormalities in toxic nonceruloplasmin (also named “free”) copper, proposing Zinc therapy as a valid tool against AD, as it has already proven to be in Wilson's disease. The perspective that comes out of his contribution (T. U. Hoogenraad 2011), for some maybe visionary or prophetic, is probably somehow adherent to the author's attitude, pragmatic, as can be expected from a physician who has dedicated his career to Wilson's disease clinical care, but also filled with enthusiasm, as demonstrated by his attitude to be prone to ideas of shifting paradigms: he was one of the pioneer of Zinc therapy in Wilson's disease. With a totally different approach, G. J. Brewer (G. J. Brewer 2011) discusses AD from an epidemiologic point of view, advancing the hypothesis that ingestion of inorganic copper from copper-made plumbing or via consumption of copper-rich dietary supplements may have a role in AD generation. Finally, the issue presents also a study connecting higher levels of copper to gender differences and cognitive status (J. F. Quinn et al., 2011). In conclusion, is copper good or bad in general for human health and in particular for cognition? Of course, the question is far from being answered in this special issue, but it is well discussed. These editors recommend reading carefully the diverse interpretations presented but also going back and read the original works which are at the basis of them. In fact, even though reliable, review articles often decrease the critical attitude of the reader, as recent publications about citation bias have pointed out [1]. Rosanna Squitti D. Larry Sparks Tjaard U. Hoogenraad George J. Brewer

Differential effects of zinc influx via AMPA/kainate receptor activation on subsequent induction of hippocampal CA1 LTP components

Zinc potentiates the induction of NMDA receptor-dependent hippocampal CA1 long-term potentiation (LTP) at low micromolar concentrations, while excessive zinc attenuates it. Homeostasis of synaptic zinc is critical for LTP induction. In the present study, LTP at hippocampal CA1 synapses was analyzed focused on the timing and level of zinc influx into hippocampal cells in hippocampal slices from young rats. Zinc (100 μM) perfusion increased intracellular zinc level and subsequently attenuated CA1 LTP induced by tetanic stimuli at 100 Hz for 1 s, which was completely inhibited in the presence of 50 μM APV, an NMDA receptor antagonist. When 10 μM CNQX, an AMPA/kainate receptor antagonist, which reduced zinc influx into hippocampal cells, was perfused prior to the zinc perfusion, the attenuation of CA1 LTP by the zinc perfusion was restored. These results suggest that facilitated zinc influx into hippocampal cells via AMPA/kainate receptor activation is an event to attenuate subsequent induction of NMDA receptor-dependent CA1 LTP. On the other hand, the zinc pre-perfusion also attenuated CA1 LTP induced by 200-Hz tetanus, but not NMDA receptor-independent CA1 LTP induced by 200-Hz tetanus in the presence of APV, suggesting that the induction of NMDA receptor-independent CA1 LTP is less susceptibility to the facilitated zinc influx into hippocampal CA1 cells. Zinc influx via AMPA/kainate receptor activation may differentially act on subsequent induction of CA1 LTP components.

High-Affinity Kainate Receptor Subunits Are Necessary for Ionotropic but Not Metabotropic Signaling

Kainate receptors signal through both ionotropic and metabotropic pathways. The high-affinity subunits, GluK4 and GluK5, are unique among the five receptor subunits, as they do not form homomeric receptors but modify the properties of heteromeric assemblies. Disruption of the Grik4 gene locus resulted in a significant reduction in synaptic kainate receptor currents. Moreover, ablation of GluK4 and GluK5 caused complete loss of synaptic ionotropic kainate receptor function. The principal subunits were distributed away from postsynaptic densities and presynaptic active zones. There was also a profound alteration in the activation properties of the remaining kainate receptors. Despite this, kainate receptor-mediated inhibition of the slow afterhyperpolarization current (I(sAHP)), which is dependent on metabotropic pathways, was intact in GluK4/GluK5 knockout mice. These results uncover a previously unknown obligatory role for the high-affinity subunits for ionotropic kainate receptor function and further demonstrate that kainate receptor participation in metabotropic signaling pathways does not require their classic role as ion channels.

Role of Ionotropic Glutamate Receptors in Long-Term Potentiation in Rat Hippocampal CA1 Oriens-Lacunosum Moleculare Interneurons

Some interneurons of the hippocampus exhibit NMDA receptor-independent long-term potentiation (LTP) that is induced by presynaptic glutamate release when the postsynaptic membrane potential is hyperpolarized. This "anti-Hebbian" form of LTP is prevented by postsynaptic depolarization or by blocking AMPA and kainate receptors. Although both AMPA and kainate receptors are expressed in hippocampal interneurons, their relative roles in anti-Hebbian LTP are not known. Because interneuron diversity potentially conceals simple rules underlying different forms of plasticity, we focus on glutamatergic synapses onto a subset of interneurons with dendrites in stratum oriens and a main ascending axon that projects to stratum lacunosum moleculare, the oriens-lacunosum moleculare (O-LM) cells. We show that anti-Hebbian LTP in O-LM interneurons has consistent induction and expression properties, and is prevented by selective inhibition of AMPA receptors. The majority of the ionotropic glutamatergic synaptic current in these cells is mediated by inwardly rectifying Ca(2+)-permeable AMPA receptors. Although GluR5-containing kainate receptors contribute to synaptic currents at high stimulus frequency, they are not required for LTP induction. Glutamatergic synapses on O-LM cells thus behave in a homogeneous manner and exhibit LTP dependent on Ca(2+)-permeable AMPA receptors.

Role of ionotropic glutamate receptors in LTP in rat hippocampal CA1 oriens-lacunosum moleculare interneurons

Event Abstract Back to Event Role of ionotropic glutamate receptors in LTP in rat hippocampal CA1 oriens-lacunosum moleculare interneurons Iris Oren1, Wiebke Nissen2, Dimitri M. Kullmann1, Peter Somogyi3 and Karri Lamsa2* 1 UCL Institute of Neurology, University College London, United Kingdom 2 Department of Pharmacology, Oxford University, United Kingdom 3 MRC Anatomical Neuropharmacology Unit, Oxford University, United Kingdom Some interneurons of the hippocampus exhibit NMDA receptor-independent long-term potentiation (LTP) that is induced by presynaptic glutamate release when the postsynaptic membrane potential is hyperpolarized. This ‘anti-Hebbian’ form of LTP is prevented by postsynaptic depolarization or by blocking AMPA and kainate receptors. Although both AMPA and kainate receptors are expressed in hippocampal interneurons, their relative roles in anti-Hebbian LTP are not known. Because interneuron diversity potentially conceals simple rules underlying different forms of plasticity, we focus on glutamatergic synapses onto a subset of interneurons with dendrites in stratum oriens and a main ascending axon that projects to stratum lacunosum-moleculare, the O-LM cells. We show that anti-Hebbian LTP in O-LM interneurons has consistent induction and expression properties, and is prevented by selective inhibition of AMPA receptors. The majority of the ionotropic glutamatergic synaptic current in these cells is mediated by inwardly rectifying Ca2+ -permeable AMPA receptors. Although GluR5-containing kainate receptors contribute to synaptic currents at high stimulus frequency, they are not required for LTP induction. Glutamatergic synapses on O-LM cells thus behave in a homogeneous manner, and exhibit LTP dependent on Ca2+-permeable AMPA receptors. Restricting attention to an identified pathway within the hippocampal inhibitory circuitry thus reveals a far more uniform pattern of synaptic physiology, pharmacology and plasticity than seen in the population of interneurons as a whole. Sampling across interneuron types could explain some of the heterogeneity reported in previous studies on plasticity in which interneuron types were not identified. Conference: 12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009. Presentation Type: Poster Presentation Topic: Research on the cerebral cortex and related structures Citation: Oren I, Nissen W, Kullmann DM, Somogyi P and Lamsa K (2009). Role of ionotropic glutamate receptors in LTP in rat hippocampal CA1 oriens-lacunosum moleculare interneurons. Front. Syst. Neurosci. Conference Abstract: 12th Meeting of the Hungarian Neuroscience Society. doi: 10.3389/conf.neuro.01.2009.04.210 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 06 Mar 2009; Published Online: 06 Mar 2009. * Correspondence: Karri Lamsa, Department of Pharmacology, Oxford University, Oxford, United Kingdom, klamsa@bio.u-szeged.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Iris Oren Wiebke Nissen Dimitri M Kullmann Peter Somogyi Karri Lamsa Google Iris Oren Wiebke Nissen Dimitri M Kullmann Peter Somogyi Karri Lamsa Google Scholar Iris Oren Wiebke Nissen Dimitri M Kullmann Peter Somogyi Karri Lamsa PubMed Iris Oren Wiebke Nissen Dimitri M Kullmann Peter Somogyi Karri Lamsa Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

ACET is a highly potent and specific kainate receptor antagonist: Characterisation and effects on hippocampal mossy fibre function

Kainate receptors (KARs) are involved in both NMDA receptor-independent long-term potentiation (LTP) and synaptic facilitation at mossy fibre synapses in the CA3 region of the hippocampus. However, the identity of the KAR subtypes involved remains controversial. Here we used a highly potent and selective GluK1 (formerly GluR5) antagonist (ACET) to elucidate roles of GluK1-containing KARs in these synaptic processes. We confirmed that ACET is an extremely potent GluK1 antagonist, with a Kb value of 1.4±0.2nM. In contrast, ACET was ineffective at GluK2 (formerly GluR6) receptors at all concentrations tested (up to 100μM) and had no effect at GluK3 (formerly GluR7) when tested at 1μM. The X-ray crystal structure of ACET bound to the ligand binding core of GluK1 was similar to the UBP310–GluK1 complex. In the CA1 region of hippocampal slices, ACET was effective at blocking the depression of both fEPSPs and monosynaptically evoked GABAergic transmission induced by ATPA, a GluK1 selective agonist. In the CA3 region of the hippocampus, ACET blocked the induction of NMDA receptor-independent mossy fibre LTP. To directly investigate the role of pre-synaptic GluK1-containing KARs we combined patch-clamp electrophysiology and 2-photon microscopy to image Ca2+ dynamics in individual giant mossy fibre boutons. ACET consistently reduced short-term facilitation of pre-synaptic calcium transients induced by 5 action potentials evoked at 20–25Hz. Taken together our data provide further evidence for a physiological role of GluK1-containing KARs in synaptic facilitation and LTP induction at mossy fibre–CA3 synapses.

B-Ephrin Reverse Signaling Is Required for NMDA-Independent Long-Term Potentiation of Mossy Fibers in the Hippocampus

The mossy fiber to CA3 pyramidal neuron synapse in the hippocampus displays an atypical form of NMDA receptor-independent long-term potentiation (LTP). Plasticity at this synapse is expressed in the presynaptic terminal as an elevated probability of neurotransmitter release. However, evidence indicates that postsynaptic mechanisms and trans-synaptic signaling through an association between postsynaptic EphB receptors and presynaptic B-ephrins are necessary for the induction of LTP. Here we show that ephrin-B3 protein is highly expressed in mossy fiber axons and terminals. There are specific deficits in mossy fiber LTP in mice in which the cytoplasmic C-terminal signaling domain of the ephrin-B3 protein is replaced with beta-galactosidase. These deficits are not observed in ephrin-B3 null mutant mice because of functional redundancy by virtue of other B-ephrins. These results indicate that B-ephrin reverse signaling into the presynaptic mossy fiber bouton is required for the induction of NMDA receptor-independent LTP at this synapse.

Long- and short-term plasticity at mossy fiber synapses on mossy cells in the rat dentate gyrus

Mossy cells give rise to the commissural and associational pathway of the dentate gyrus, and receive their major excitatory inputs from the mossy fibers of granule cells. Through these feed-back excitatory connections, mossy cells have been suggested to play important roles in both normal signal processing in learning and memory, as well as in seizure propagation. However, the nature of the activity-dependent modifications of the mossy fiber inputs to mossy hilar cells is not well understood. We studied the long- and short-term plasticity properties of the mossy fiber-mossy cell synapse, using the minimal stimulation technique in slices in whole cell recorded mossy cells retrogradely prelabeled with the fluorescent dye DiO from the contralateral dentate gyrus. Following tetanic stimulation, mossy fiber synapses showed significant NMDA receptor-independent long-term potentiation (LTP), associated with increased excitatory postsynaptic currents (EPSC) amplitude and decreased failure rates. Coefficient of variance and failure rate analyses suggested a presynaptic locus of LTP induction. Mossy fiber synapses on mossy cells also showed activity-dependent short-term modification properties, including both frequency-dependent facilitation (stimuli at higher frequencies evoked larger EPSCs with lower failure rates) and burst facilitation (each EPSC in a burst had a larger amplitude and higher probability of occurrence than the preceding EPSCs within the burst). The data show that mossy fiber-mossy cell synapses exhibit both long- and short-term plasticity phenomena that are generally similar to the mossy fiber synapses on CA3 pyramidal cells.

Attenuated plasticity of postsynaptic kainate receptors in hippocampal CA3 pyramidal neurons.

Kainate receptor-mediated components of postsynaptic currents at hippocampal mossy fiber synapses have markedly slower kinetics than currents arising from AMPA receptors. Here, we demonstrate that other aspects of kainate and AMPA receptor function at this synapse are distinct; in particular, kainate receptor currents are less sensitive to short- and long-term increases in presynaptic strength. EPSCs arising predominantly from AMPA receptors exhibited well characterized paired-pulse facilitation, frequency facilitation, and NMDA receptor-independent long-term potentiation, whereas isolated kainate receptor synaptic currents (KA-EPSCs) exhibited attenuated facilitation and long-term potentiation. In addition, KA-EPSCs varied in their sensitivity to a low-affinity competitive antagonist, suggestive of a synaptic heterogeneity greater than that of EPSCs comprised predominantly of AMPA receptors. These data suggest that the proportional contribution of AMPA and kainate receptors to ensemble synaptic currents will vary depending on the firing frequency of mossy fiber afferents. These synaptic features may be a mechanism for limiting activation of kainate receptors at mossy fiber synapses, which has been shown to be involved in seizurogenic firing of the CA3 network.

Long-term potentiation in the hippocampal CA1 area and dentate gyrus plays different roles in spatial learning.

NMDA receptor-dependent long-term potentiation (LTP) at hippocampal synapses has been considered a crucial component of the cellular basis for learning and memory. This form of LTP occurs in excitatory synapses in both the CA1 area and the dentate gyrus in the hippocampus. However, differential roles of LTP in these areas have not yet been identified. To address this issue, we enhanced the degree of LTP by expressing Ca2+-permeable AMPA receptors at either hippocampal CA1 or dentate gyrus synapses using Sindbis viral vectors (SINs) encoding both green fluorescent proteins and unedited GluR2 (GluR2Q) subunits, and examined their effects on rat spatial learning. The viral vectors were locally injected into the 8-week-old-rat brain in vivo bilaterally. The postsynaptic expression of Ca2+-permeable AMPA receptors enhanced the degree of LTP, and induced NMDA receptor-independent LTP in the presence of the NMDA receptor antagonist in SIN-infected regions in both CA1 and dentate gyrus in hippocampal slice preparations. However, the regional expression of Ca2+-permeable AMPA receptors caused opposite behavioural consequences on the Morris water maze task: rats with SIN-infected CA1 pyramidal cells showed shorter escape latency and better probe test performance, whereas those with SIN-infected dentate gyrus granule cells showed impaired performance. Thus, it was demonstrated that CA1 and dentate gyrus synapses play different functional roles in spatial learning despite their similar mechanism for LTP induction.

Presynaptic Ca2+Entry Is Unchanged during Hippocampal Mossy Fiber Long-Term Potentiation

The hippocampal mossy fiber (MF)-CA3 synapse exhibits NMDA receptor-independent long-term potentiation (LTP), which is expressed by presynaptic mechanisms leading to persistent enhancement of transmitter release. Recent studies have identified several molecules that may play an important role in MF-LTP. These include Rab3A, RIM1alpha, kainate autoreceptor, and hyperpolarization-activated cation channel (I(h)). However, the precise cellular expression mechanism remains to be determined because some studies noticed essential roles of release machinery molecules, whereas others suggested modulation of the ionotropic processes affecting Ca2+ entry into the presynaptic terminals. Using fluorescence recordings of presynaptic Ca2+ in hippocampal slices, here we demonstrated that MF-LTP is not accompanied by an increase in presynaptic Ca2+ influx during an action potential. Whole-cell recordings from CA3 neurons revealed long-lasting increases in mean frequency, but not mean amplitude, of miniature EPSCs after the high-frequency stimulation of MFs. These data indicate that the presynaptic expression mechanisms responsible for enhanced transmitter release during MF-LTP involve persistent modification of presynaptic molecular targets residing downstream of Ca2+ entry.