Academic literature on the topic 'Memory; Hippocampus; NMDA receptor antagonists'

CRH, the primary regulator of the neuroendocrine responses to stress, has been shown to modulate synaptic efficacy and the process of learning and memory in hippocampus. However, effects of CRH on N-methyl-d-aspartate (NMDA) receptor, the key receptor for synaptic plasticity, remain unclear. In primary cultured hippocampal neurons, using the technique of whole-cell patch-clamp recordings, we found that CRH (1 pmol/liter to 10 nmol/liter) inhibited NMDA-induced currents in a dose-dependent manner. This effect was reversed by the CRH receptor type 1 (CRHR1) antagonist antalarmin but not by the CRHR2 antagonist astressin-2B, suggesting that CRHR1 mediated the inhibitory effect of CRH. Investigations on the signaling pathways of CRH showed that CRH dose-dependently induced phosphorylated phospholipase C (PLC)-β3 expression and increased intracellular cAMP content in these cells. Blocking PLC activity with U73122 prevented CRH-induced depression of NMDA current, whereas blocking protein kinase A (H89) and adenylate cyclase (SQ22536) failed to affect the CRH-induced depression of NMDA current. Application of inositol-1,4,5-triphosphate receptor (IP3R) antagonist, Ca2+ chelators or protein kinase C (PKC) inhibitors also mainly blocked CRH-induced depression of NMDA currents, suggesting involvement of PLC/IP3R/Ca2+and PLC/PKC signaling pathways in CRH down-regulation of NMDA receptors. Our results suggest that CRH may exert neuromodulatory actions on hippocampus through regulating NMDA receptor function.

Abstract Dopamine modulates cognitive functions through regulation of synaptic transmission and plasticity in the hippocampus and prefrontal cortex (PFC). Thus, dopamine dysfunction in depression may be particularly relevant for the cognitive symptoms. The norepinephrine transporter inhibitor reboxetine facilitates memory processing in both healthy volunteers and in depressed patients and increases dopamine release in both the hippocampus and PFC. We investigated the potential involvement of the hippocampal and PFC dopamine D1/5 receptors in the cognitive effects of reboxetine using the object recognition test in rats. Infusion of the D1/5 antagonist SCH23390 into the dorsal hippocampus or medial PFC prior to the exploration of the objects impaired memory. Conversely, infusion of the D1/5 agonist SKF81297 into the dorsal hippocampus or medial PFC facilitated memory. Reboxetine similarly facilitated recognition memory in healthy rats and the D1/5 antagonist SCH23390 reversed this effect when infused into the dorsal PFC, but not when infused into the hippocampus. Moreover, systemic reboxetine increased the levels of the NMDA subunit GluN2A in the PFC but not in the hippocampus. Finally, we demonstrate that a single dose of reboxetine does not affect immobility in the forced swim test but improves recognition memory in the Flinders sensitive line (FSL) rat model for depression. The present data in rats are in line with effects of reboxetine on memory formation in healthy volunteers and depressed patients and indicate the involvement of PFC dopamine D1/5 receptors.

Background: Abnormalities in neural oscillations that occur in the gamma frequency range (30–80 Hz) may underlie cognitive deficits in schizophrenia. Both cognitive impairments and gamma oscillatory disturbances can be induced in healthy people and rodents by administration of N-methyl-D-aspartate receptor (NMDAr) antagonists. Aims: We studied relationships between cognitive impairment and gamma abnormalities following NMDAr antagonism, and attempted to reverse deficits with the metabotropic glutamate receptor type 2/3 (mGluR2/3) agonist LY379268. Methods: C57/Bl6 mice were trained to perform the Trial-Unique Nonmatching to Location (TUNL) touchscreen test for working memory. They were then implanted with local field potential (LFP) recording electrodes in prefrontal cortex and dorsal hippocampus. Mice were administered either LY379268 (3 mg/kg) or vehicle followed by the NMDAr antagonist MK-801 (0.3 or 1 mg/kg) or vehicle prior to testing on the TUNL task, or recording LFPs during the presentation of an auditory stimulus. Results: MK-801 impaired working memory and increased perseveration, but these behaviours were not improved by LY379268 treatment. MK-81 increased the power of ongoing gamma and high gamma (130–180 Hz) oscillations in both brain regions and regional coherence between regions, and these signatures were augmented by LY379268. However, auditory-evoked gamma oscillation deficits caused by MK-801 were not affected by LY379268 pretreatment. Conclusions: NMDA receptor antagonism impairs working memory in mice, but this is not reversed by stimulation of mGluR2/3. Since elevations in ongoing gamma power and regional coherence caused by MK-801 were improved by LY379268, it appears unlikely that these specific oscillatory abnormalities underlie the working memory impairment caused by NMDAr antagonism.

The effect of N-methyl-d-aspartate (NMDA) and 2-(aminomethyl)phenylacetic acid/kainate (AMPA/kainate) glutamate receptors on dentate cell proliferation and hippocampal synapsin-I induction was examined after global ischemia. Cell proliferation was assessed using BrdU labeling, and synaptic responses were assessed using synapsin-I expression, Systemic glutamate receptor antagonists (MK-801 and NBQX) increased BrdU-labeled cells in the dentate subgranular zone (SGZ) of control adult gerbils (30% to 90%, P < 0.05). After global ischemia (at 15 days after 10 minutes of ischemia), most CA1 pyramidal neurons died, whereas the numbers of BrdU-labeled cells in the SGZ increased dramatically (>1000%, P < 0,0001). Systemic injections of MK801 or NBQX, as well as intrahippocampal injections of either drug, when given at the time of ischemia completely blocked the birth of cells in the SGZ and the death of CA1 pyramidal neurons at 15 days after ischemia. Glutamate receptor antagonists had little effect on cell birth and death when administered 7 days after ischemia. The induction of synapsin-I protein in stratum moleculare of CA3 at 7 and 15 days after global ischemia was blocked by pretreatment with systemic or intrahippocampal MK-801 or NBQX. It is proposed that decreased dentate glutamate receptor activation—produced by glutamate receptor antagonists in normal animals and by chronic ischemic hippocampal injury—may trigger dentate neurogenesis and synaptogenesis. The synapsin-I induction in mossy fiber terminals most likely represents re-modeling of dentate granule cell neuron presynaptic elements in CA3 in response to the ischemia. The dentate neurogenesis and synaptogenesis that occur after ischemia may contribute to memory recovery after hippocampal injury caused by global ischemia.

Memory is measured by measuring retrieval. Retrieval is often triggered by the conditioned stimulus (CS); however, as known since Pavlov, presentation of the CS alone generates extinction. One-trial avoidance (IA) is a much used conditioned fear paradigm in which the CS is the safe part of a training apparatus, the unconditioned stimulus (US) is a footshock and the conditioned response is to stay in the safe area. In IA, retrieval is measured without the US, as latency to step-down from the safe area (i.e., a platform). Extinction is installed at the moment of the first unreinforced test session, as clearly shown by the fact that many drugs, including PKA, ERK and protein synthesis inhibitors as well as NMDA receptor antagonists, hinder extinction when infused into the hippocampus or the basolateral amygdala at the moment of the first test session but not later. Some, but not all the molecular systems required for extinction are also activated by retrieval, further endorsing the hypothesis that although retrieval is behaviorally and biochemically necessary for the generation of extinction, this last process constitutes a new learning secondary to the unreinforced expression of the original trace.

Allocentric spatial learning can sometimes occur in one trial. The incorporation of information into a spatial representation may, therefore, obey a one–trial correlational learning rule rather than a multi–trial error–correcting rule. It has been suggested that physiological implementation of such a rule could be mediated by N –methyl–D–aspartate (NMDA) receptor–dependent long–term potentiation (LTP) in the hippocampus, as its induction obeys a correlational type of synaptic learning rule. Support for this idea came originally from the finding that intracerebral infusion of the NMDA antagonist AP5 impairs spatial learning, but studies summarized in the first part of this paper have called it into question. First, rats previously given experience of spatial learning in a watermaze can learn a new spatial reference memory task at a normal rate despite an appreciable NMDA receptor blockade. Second, the classical phenomenon of ‘blocking’ occurs in spatial learning. The latter finding implies that spatial learning can also be sensitive to an animal's expectations about reward and so depend on more than the detection of simple spatial correlations. In this paper a new hypothesis is proposed about the function of hippocampal LTP. This hypothesis retains the idea that LTP subserves rapid one–trial memory, but abandons the notion that it serves any specific role in the geometric aspects of spatial learning. It is suggested that LTP participates in the ‘automatic recording of attended experience’: a subsystem of episodic memory in which events are temporarily remembered in association with the contexts in which they occur. An automatic correlational form of synaptic plasticity is ideally suited to the online registration of context–event associations. In support, it is reported that the ability of rats to remember the most recent place they have visited in a familiar environment is exquisitely sensitive to AP5 in a delay–dependent manner. Moreover, new studies of the lasting persistence of NMDA–dependent LTP, known to require protein synthesis, point to intracellular mechanisms that enable transient synaptic changes to be stabilized if they occur in close temporal proximity to important events. This new property of hippocampal LTP is a desirable characteristic of an event memory system.

N-methyl-D-aspartate receptor (NMDAR) antagonists have been found to be effective to inhibit morphine dependence. However, the discovery of the selective antagonist for NMDAR GluN2B with low side-effects still remains challenging. In the present study, we report a selective NMDAR GluN2B antagonist con-T[M8Q](a conantokin-T variant) that potently inhibits the naloxone-induced jumping and conditioned place preference of morphine-dependent mice at nmol/kg level, 100-fold higher than ifenprodil, a classical NMDAR NR2B antagonist. Con-T[M8Q] displays no significant impacts on coordinated locomotion function, spontaneous locomotor activity, and spatial memory mice motor function at the dose used. Further molecular mechanism experiments demonstrate that con-T[M8Q] effectively inhibited the transcription and expression levels of signaling molecules related to NMDAR NR2B subunit in hippocampus, including NR2B, p-NR2B, CaMKII-α, CaMKII-β, CaMKIV, pERK, and c-fos. The high efficacy and low side effects of con-T[M8Q] make it a good lead compound for the treatment of opiate dependence and for the reduction of morphine usage.

Yu, Tzu-Ping and Cui-Wei Xie. Orphanin FQ/nociceptin inhibits synaptic transmission and long-term potentiation in the rat dentate gyrus through postsynaptic mechanisms. J. Neurophysiol. 80: 1277–1284, 1998. Orphanin FQ/nociceptin (OFQ), a recently characterized natural ligand for the opioid receptor-like 1 (ORL1) receptor, shares structural similarity to the endogenous opioids. Our previous study found that OFQ, like classical opioids, modulated synaptic transmission and long-term potentiation (LTP) in the hippocampal CA1 region, suggesting a modulatory role for OFQ in synaptic plasticity involved in learning and memory. In the present study we investigated the action of OFQ in the dentate gyrus and explored possible underlying cellular mechanisms. Field potential recordings showed that OFQ significantly inhibited excitatory synaptic transmission and LTP induction in the dentate lateral perforant path. In the presence of OFQ, the excitatory postsynaptic potential (EPSP) slope-population spike (E-S) curve was shifted to the right, and no significant change was found in paired-pulse facilitation, suggesting a postsynaptic mechanism responsible for the inhibition of synaptic transmission. Under whole cell voltage-clamp conditions, bath application of OFQ activated K+ currents in most granule cells tested at a holding potential of −50 mV, suggesting that OFQ could reduce the excitability of dentate granule cells by hyperpolarizing cell membranes. OFQ also inhibited the amplitude of N-methyl-d-aspartate (NMDA) receptor–mediated excitatory postsynaptic currents (EPSCs) without affecting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor–mediated EPSCs. This inhibition was not blocked by opioid receptor antagonists. Furthermore, the inward currents evoked by focal application of NMDA to granule cells were suppressed by OFQ in a dose-dependent manner, suggesting that OFQ may suppress LTP by inhibiting the function of postsynaptic NMDA receptors. These results demonstrate that OFQ may negatively modulate synaptic transmission and plasticity in the dentate gyrus through postsynaptic mechanisms, including hyperpolarization of granule cells as well as inhibition of the function of postsynaptic NMDA receptors/channels in dentate granule cells.

Abstract Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disease characterized by a complex neuropsychiatric syndrome in association with an antibody-mediated decrease of NMDAR. About 85% of patients respond to immunotherapy (and removal of an associated tumour if it applies), but it often takes several months or more than 1 year for patients to recover. There are no complementary treatments, beyond immunotherapy, to accelerate this recovery. Previous studies showed that SGE-301, a synthetic analogue of 24(S)-hydroxycholesterol, which is a potent and selective positive allosteric modulator of NMDAR, reverted the memory deficit caused by phencyclidine (a non-competitive antagonist of NMDAR), and prevented the NMDAR dysfunction caused by patients’ NMDAR antibodies in cultured neurons. An advantage of SGE-301 is that it is optimized for systemic delivery such that plasma and brain exposures are sufficient to modulate NMDAR activity. Here, we used SGE-301 to confirm that in cultured neurons it prevented the antibody-mediated reduction of receptors, and then we applied it to a previously reported mouse model of passive cerebroventricular transfer of patient’s CSF antibodies. Four groups were established: mice receiving continuous (14-day) infusion of patients’ or controls’ CSF, treated with daily subcutaneous administration of SGE-301 or vehicle (no drug). The effects on memory were examined with the novel object location test at different time points, and the effects on synaptic levels of NMDAR (assessed with confocal microscopy) and plasticity (long-term potentiation) were examined in the hippocampus on Day 18, which in this model corresponds to the last day of maximal clinical and synaptic alterations. As expected, mice infused with patient’s CSF antibodies, but not those infused with controls’ CSF, and treated with vehicle developed severe memory deficit without locomotor alteration, accompanied by a decrease of NMDAR clusters and impairment of long-term potentiation. All antibody-mediated pathogenic effects (memory, synaptic NMDAR, long-term potentiation) were prevented in the animals treated with SGE-301, despite this compound not antagonizing antibody binding. Additional investigations on the potential mechanisms related to these SGE-301 effects showed that (i) in cultured neurons SGE-301 prolonged the decay time of NMDAR-dependent spontaneous excitatory postsynaptic currents suggesting a prolonged open time of the channel; and (ii) it significantly decreased, without fully preventing, the internalization of antibody-bound receptors suggesting that additional, yet unclear mechanisms, contribute in keeping unchanged the surface NMDAR density. Overall, these findings suggest that SGE-301, or similar NMDAR modulators, could potentially serve as complementary treatment for anti-NMDAR encephalitis and deserve future investigations.

Memory of some forms requires the hippocampus, a brain structure in the medial temporal lobe that reveals remarkable synaptic plasticity. Most synapses in the hippocampus require NMDA-receptors for the induction of this plasticity. Memories that require the hippocampus may also require NMDA-receptor mediated plasticity. This thesis tested the involvement of NMDA receptor activity in memory for a non-spatial, social learning task that requires the hippocampus: the social transmission of food preference, NMDA receptor antagonist (CPP) injected systemically 55 minutes prior to training impaired performance 72 hours later, but not 48 hours, 24 hours, or 15 minutes later. NMDA receptor antagonist (AP-5) injected into the dorsal hippocampus 30 minutes prior to training also impaired performance at the 72-hour delay. Injections of CPP at 10 minutes or 24 hours post-training had no effect on performance. These results suggest that hippocampal NMDA receptor activity is necessary for stable learning of the non-spatial social transmission of food preference.

Post-traumatic stress disorder (PTSD) is a severe anxiety disorder affecting cognitive function. 1 in 4 individuals exposed to a life-threatening event may develop PTSD, which is characterised by symptoms of hyperarousal, avoidance and intrusions. Although treatment is effective in most cases, the response is far from satisfactory. It is now clear that novel drug treatment and a better understanding of the neurobiology of PTSD are necessary if we are to realise a better response and treatment outcome in these patients. Glutamatergic pathways play an important role in cognition, while recent studies have emphasized a causal role for glutamate in PTSD, and of the potential value of glutamate receptor modulators in treating the disorder. Stress-related elevation in glutamate exerts detrimental effects on cognition, especially via activation of the N-methyl-D-aspartate (NMDA) receptor, and has been implicated in PTSD associated cognitive deficits. Recently, the cr-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor has been found to exert a modulatory action on NMDA receptor function. Ampakines are positive allosteric modulators of the AMPA receptor, and have demonstrated beneficial effects in animal models of learning as well as antidepressant action, and to improve short-term memory in humans. The aims of this study were firstly to study the effects of the ampakine, Org 26576, on spatial memory performance in healthy male Sprague-Dawley rats. Secondly, since PTSD is associated with pronounced deficits in cognition, we studied the ability of Org 26576 to modify stress-evoked spatial memory deficits in rats subjected to single prolonged stress (SPS), a putative animal model of PTSD. In both cases, neuroreceptor studies were performed to determine any relationship between hippocampal and cortical NMDA receptor binding characteristics and effects on spatial memory performance. After exposure of the animals to either normal handling or SPS conditions, spatial memory performance was assessed using a 5 day memory acquisition and consolidation protocol in a modified version of the Morris water maze (MWM). Experimental and control groups both received either saline (1 ml/kg i.p.) or Org 26576 at incremental doses of 1, 3 or 10 mg/kg intraperitoneally twice daily for 12 days. Separate groups of animals were used for the neuroreceptor studies, except that behavioural testing was not performed. 24hrs after drug treatment discontinuation, the animals were sacrificed and frontal cortex and hippocampus removed for NMDA receptor binding analysis. In normal rats, Org 26576 3 mg/kg and 10 mg/kg exerted a short-lasting reduction in escape latency on day 1, but which lost prominence over the subsequent training days. Org 26576 1, 3 and 10 mg/kg, however, significantly improved spatial memory retrieval on day 5. No changes in frontal cortical or hippocampal NMDA receptors were observed. Contrary to expected, rats subjected to SPS failed to express noteworthy deficits in spatial memory as previously described. Treatment of SPS-exposed animals with Org 26576 did not significantly alter spatial learning evident in SPS animals on day 1 of acquisition training, as well as on subsequent training days. Org 26576 1 mg/kg increased spatial memory retrieval compared to the unstressed saline control, but not compared to the SPS group. Org 26576 only at a dose of 1 mg/kg decreased cortical, but not hippocampal NMDA receptor density (Bmax) in SPS animals versus unstressed but not saline treated SPS animals. No changes in receptor affinity (Kd) were noted. Org 26576 therefore improves early initial spatial learning in healthy rats, but exerts a lesser effect on memory consolidation over the remainder of the training period. However, Org 26576 significantly improves retrieval of spatial memory without simultaneous changes in frontal cortical and hippocampal NMDA receptor binding. Org 26576 thus may benefit both short-term and long-term memory processes in normal animals without effects on limbic NMDA receptor binding, and provides a rationale for testing in conditions that present with cognitive disturbances. However, the SPS model failed to engender marked deficits in spatial memory performance; this result ultimately complicated the interpretation of the combined stress-drug treatment studies. Studies in healthy animals therefore conclude that Org 26576 is an effective agent to enhance long-term memory processes and should be investigated further for its possible application in disorders of cognition. Although the value of Org 26576 in an animal model of PTSD were inconclusive, further studies in SPS and other PTSD models, as well as models of relevance for schizophrenia, Alzheimer's disease and depression, are encouraged.
Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2009.

Orientadores: Elenice Aparecida de Moraes Ferrari, Luiz Roberto Giorgetti Britto
Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: O presente estudo investigou os efeitos do antagonista do receptor NMDA, MK-801 na expressão do produto do zenk no hipocampo (Hp) de pombos, submetidos ao condicionamento clássico aversivo. Antes do treino, administrou-se MK-801, i.p, para o grupo condicionado MK (GCMK, n=6), salina para o grupo condicionado salina (GCS, n=6) e nenhum tratamento para os grupos-controle: randômico (GCR, n=6), contexto (GCC=7) e manipulação (GM=4). GCMK e GCS receberam três associações de som (1000-Hz, 83 dB,1 s) e choque (10 mA, 35ms) numa sessão de 20 min. Para GCR os estímulos foram aleatórios e o GCC não recebeu estímulos. O teste de re-exposição ao contexto ocorreu 24 h após o treino. A análise de freezing no treino mostrou maior ocorrência para o GCS em comparação ao GCC (p<0,05), com aumento gradual na sessão (p<0,01). No teste, GCS expressou maior ocorrência de freezing em comparação a todos os grupos (p<0,001). A expressão de zenk foi avaliada por imuno-histoquímica. O GCS teve maior número de núcleos ZENK-positivos no Hp ventral, especificamente no Hp ventro-medial, comparativamente aos outros grupos (p<0,01). A baixa ocorrência de freezing ao contexto no GCMK evidencia o efeito amnésico do MK-801. A análise da marcação de núcleos ZENK-positivos no Hp sugeriu sua ativação regionalizada na evocação de memória contextual aversiva em pombos. O presente estudo indica o envolvimento de receptores de glutamato do tipo NMDA em mecanismos sinápticos de plasticidade neural durante a evocação de memória aversiva ao contexto. Palavras-chave: condicionamento clássico aversivo, hipocampo, MK-801, antagonista dos receptores NMDA, recuperação da memória aversiva, zenk
Abstract: The present study investigated the effects of the antagonist of the glutamate NMDA receptor, MK- 801, in the activation of zenk in the hippocampus of pigeons (Hp) submitted to the classical aversive conditioning. Two groups of pigeons received MK-801 (MKG, n=6) or saline (SG, n=6) 30 min before training with tone-shock associations. The control groups received unpaired stimulation (RCG, n=6), exposure to the context (CCG=7) or manipulation alone (MG=4). During the 20 min training session MKG and SG received three sound (1000-Hz, 83 dB, 1 s) and shock associations (10 mA, 35ms). The test to the context occurred 24 hours after the training. During the training session SG animals showed more freezing as compared with CCG (p<0,05). During the test, SG expressed higher freezing than all the other groups (p<0,001). ZENK analysis was conducted with imunohistochemistry. The density of ZENK-positive nuclei in the ventral hippocampus, specifically in the ventromedial hippocampus, was higher for SG as compared to the other groups (p<0,01). The fact that the animals from the MKG expressed lower freezing to the context may be considered as indicative of an amnesic effect of the MK-801. The density of ZENK-positive nuclei in the hippocampus suggests a regional activation that may be related to the retrieval of contextual aversive memory. The present study indicates that synaptic mechanisms mediated by NMDA glutamate receptors participate in the neural plasticity related to the retrieval of contextual aversive memory
Mestrado
Fisiologia
Mestre em Biologia Funcional e Molecular

Initialement encodés dans l’hippocampe, les nouveaux souvenirs déclaratifs deviennent progressivement dépendants d’un réseau distribué de neurones corticaux au cours de leur maturation dans le temps. Cependant, les mécanismes cellulaires et moléculaires sous-­‐tendant la consolidation et le stockage à long terme de ces nouveaux souvenirs au sein des réseaux corticaux restent à élucider. Les récepteurs N-­‐méthyl-­‐D-­‐aspartate (RNMDA) jouent un rôle essentiel dans l’induction et la régulation des changements synaptiques sous-­‐tendant les processus mnésiques de type associatifs. Sur la base de leurs propriétés biophysiques respectives, nous avons formulé l’hypothèse que la redistribution synaptique des deux formes principales de sous-­‐unités GluN2 exprimées dans le néocortex adulte (GluN2A and GluN2B), pourrait constituer un mécanisme de régulation de la plasticité synaptique supportant l’intégration et la stabilisation progressive des souvenirs au niveau cortical au cours du processus de consolidation mnésique. En combinant, chez le rat adulte, une approche comportementale, biochimique, pharmacologique et des stratégies innovantes consistant à manipuler le trafic de sous-­‐unités des RNMDA à la surface synaptique, nos résultats mettent en évidence un changement cortical dans la composition synaptique en sous unités GluN2, lequel régule la stabilisation progressive de la mémoire à long terme au sein des réseaux corticaux. Nous avons d'abord établi que les RNMDA contenant la sous-­‐unité GluN2B, via leur interaction spécifique avec une protéine clé de la signalisation synaptique, la CaMKII, sont préférentiellement recrutés lors de la phase d’encodage pour permettre l’allocation des nouveaux souvenirs olfactifs associatifs dans un réseau de neurones corticaux spécifique. Au cours du processus de consolidation, nous avons révélé que la redistribution des RNMDA corticaux contenant les sous-­‐unités GluN2B vers l’extérieur ou l’intérieur de l’espace synaptique suite à l’apprentissage, contrôle respectivement la stabilisation de la mémoire à long terme et son oubli au cours du temps. Enfin, renforcer l’acquisition initiale conduit à une augmentation plus rapide du ratio post-­‐synaptique GluN2A/GluN2B et accélère la cinétique du dialogue hippocampo-­‐cortical, ce qui se traduit par une stabilisation accélérée des souvenirs au sein des réseaux corticaux. Pris dans leur ensemble, nos travaux montrent que le trafic des GluN2B-­‐RNMDA corticaux représente un mécanisme cellulaire majeur conditionnant le devenir des traces mnésiques (i.e. stabilisation versus oubli) et apporte un éclairage nouveau sur la façon dont le cerveau organise les souvenirs récents et anciens
Initially encoded in the hippocampus, new declarative memories are thought to become progressively dependent on a broadly distributed cortical network as they mature and consolidate over time. Although we have a good understanding of the mechanisms underlying the formation of new memories in the hippocampus, little is known about the cellular and molecular mechanisms by which recently acquired information is transformed into remote memories at the cortical level. The N-­‐methyl-­‐D-­‐aspartate receptor (NMDAR) is widely known to be a key player in many aspects of long-­‐term experience-­‐dependent synaptic changes underlying associative memory processes. Based on their distinct biophysical properties, we postulated that the activity-­‐dependent surface dynamics of the two predominant GluN2 subunits (GluN2A and GluN2B) of NMDARs present in the adult neocortex could provide a metaplastic control of synaptic plasticity supporting the progressive embedding and stabilization of long-­‐lasting associative memories within cortical networks during memory consolidation. By combining, in adult rats, behavioral, biochemical, pharmacological and innovative strategies consisting in manipulating trafficking of NMDAR subunits at the cell membrane, our results identify a cortical switch in the synaptic GluN2-­‐containing NMDAR composition which drives the progressive embedding and stabilization of long-­‐lasting memories within cortical networks. We first established that cortical GluN2B-­‐containing NMDARs and their specific interactions with the synaptic signaling CaMKII protein are preferentially recruited upon encoding of associative olfactory memories to enable neuronal allocation, the process via which a new memory trace is thought to be allocated to a given neuronal network. As these memories are progressively processed and embedded into cortical networks, we observed a learning-­‐induced surface redistribution of cortical GluN2B-­‐containing NMDARs outwards or inwards synapses which respectively drives the progressive stabilization and subsequent forgetting of remote memories over time. Finally, increasing the strength, upon encoding, of the initial memory leads to a faster increase of the cortical GluN2A/GluN2B synaptic ratio and accelerates the kinetics of hippocampal-­‐cortical interactions, which translated into a faster stabilization of memories within cortical networks. Taken together, our results provide evidence that GluN2B-­‐NMDAR surface trafficking controls the fate of remote memories (i.e. stabilization versus forgetting), shedding light on a novel mechanism used by the brain to organize recent and remote memories

Im Subikulum der Ratte finden sich zwei unterschiedliche Typen von Pyramidalzellen, die sich auf Grund ihres intrinsischen Entladungsverhaltens unterscheiden. Die Funktion dieser beiden Zelltypen hinsichtlich der synaptischer Neurotransmission ist unklar. Bursterzellen und regulär feuernde Zellen zeigten nach tetanischer Reizung ein unterschiedliches Ausmaß der LTP. Neben der zellspezifischen Ausprägung der LTP fanden sich mehrere Hinweise auf eine zielspezifische Projektion der Efferenzen der vorgeschalteten Area CA1. Die durchgeführten Experimente legen den Schluss nahe, dass Axone von Pyramidalzellen der Area CA1 selektiv auf subikuläre Pyramidenzellen projizieren und so den hippokampalen Informationsfluss steuern und regulieren können. NMDA-Rezeptoren auf beiden Seiten des synaptischen Spaltes spielen hier eine besondere Rolle. Präsynaptische NMDAR der Untereinheit NR2B scheinen an der LTP in Bursterzellen beteiligt zu sein und über einen vermehrten Kalziumeinstrom in die Präsynapse eine langanhaltende Erhöhung der Transmitterausschüttung herbeizuführen. Ebenso zeigten sich abhängig von der Zielzelle Hinweise auf eine unterschiedliche Aktivierung der präsynaptischen Adenylylcyclase-cAMP Kaskade. In Pilokarpin-behandelten Tieren ließ sich nach hochfrequenter Reizung keine langanhaltende Potenzierung der synaptischen Antworten nachweisen. Stattdessen scheinen polysynaptisch latente Verbindungen mittels tetanischer Stimulation aktivierbar zu sein. In einigen Fällen waren diese polysynaptisch latenten Verbindungen per se, in anderen Fällen nach Blockade der GABAergen Neurotransmission aktiv. In Hirnschnittpräparaten von Patienten mit pharmakoresistenter Temporallappenepilepsie konnte im Subikulum spontane rhythmische Aktivität mit einer Frequenz von 0,75 bis 3 Hz aufgezeichnet werden. Diese Aktivität, bestehend aus EPSP/IPSP Sequenzen, wurde sowohl in sklerotischem als auch in nicht sklerotischem Gewebe gefunden. In beiden Gruppen korrelierte die in vitro Aktivität sehr gut mit dem präoperativen Auftreten elektroenzephalografisch detektierter interiktaler Aktivität. Die Blockade GABAerger oder glutamaterger Neurotransmission hob die inhibitorische bzw. exzitatorische Aktivität auf. Dies legt den Schluss nahe, dass sowohl Interneurone wie Pyramidalzellen an der spontanen rhythmischen Aktivität beteiligt sind.
The subiculum plays a key role in processing memory information from the hippocampus to different cortical and subcortical brain regions. Subicular pyramidal cells are classified as regular firing or bursting cells according to their responses to supra-threshold depolarizing current pulses. Synaptic terminals arising from CA1 pyramidal cells do not function as a single compartment but show a specialized synaptic plasticity onto subicular pyramidal cells depending on the discharge properties of the synaptic target. Tetanic stimulation of CA1 axons caused a significantly stronger long-term potentiation (LTP) in bursting cells than in regular firing cells. Postsynaptic bursting was not necessary for the enhanced synaptic potentiation in bursting cells. The LTP in bursting neurons was independent of postsynaptic calcium, induced by presynaptic NR2B-containing autoreceptors and mediated via a adenylyl cylcase-cAMP-dependent signaling cascade. In pilocarpine-treated animals subicular LTP was impaired. A long-lasting increase in synaptic transmission could not be observed after titanic stimulation neither in regular firing cells nor in bursting cells. In human brain slices resected from patients from with drug-resistant temporal lobe epilepsy the subiculum displayed spontaneous rhythmic activity. In sclerotic but also in non-sclerotic hippocampal tissue the subiculum showed cellular and synaptic changes which suffice to generate spontaneous rhythmic activity that is correlated with the occurrence and frequency of interictal discharges recorded in the electroencephalograms of the corresponding patients.