Rapid and Transient Learning-Associated Increase in NMDA NR1 Subunit in the Rat Hippocampus (original) (raw)
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Neurochemical …, 2006
Adult male Wistar rats were given either a single training trial or one training trial per day during 3 days followed by a retention test trial in an inhibitory avoidance (IA) task. In animals given a single training trial, pretraining, but not pretest bilateral infusion of the NMDA glutamate receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP5) (5.0 lg) into the CA1 hippocampal area blocked IA retention. In animals given three training trials, infusions of AP5 given prior to each of the three training trials severely impaired, but did not block retention. The results indicate that NMDA receptors in the hippocampus are involved in the formation, but not in expression, of aversive memory. In addition, rats given repeated training were able to show a mild improvement of performance across training trials, possibly through mechanisms that do not depend on NMDA receptor activation in the dorsal hippocampus.
Hippocampal NMDA receptors and the previous experience effect on memory
Journal of Physiology-Paris, 2014
N-methyl-D-aspartate receptors (NMDAR) are thought to be responsible for switching synaptic activity specific patterns into long-term changes in synaptic function and structure, which would support learning and memory. Hippocampal NMDAR blockade impairs memory consolidation in rodents, while NMDAR stimulation improves it. Adult rats that explored twice an open field (OF) before a weak though overthreshold training in inhibitory avoidance (IA), expressed IA long-term memory in spite of the hippocampal administration of MK-801, which currently leads to amnesia. Those processes would involve different NMDARs. The selective blockade of hippocampal GluN2Bcontaining NMDAR with ifenprodil after training promoted memory in an IA task when the training was weak, suggesting that this receptor negatively modulates consolidation. In vivo, after 1 h of an OF exposure-with habituation to the environment-, there was an increase in GluN1 and GluN2A subunits in the rat hippocampus, without significant changes in GluN2B. Coincidentally, in vitro, in both rat hippocampal slices and neuron cultures there was an increase in GluN2A-NMDARs surface expression at 30 min; an increase in GluN1 and GluN2A levels at about 1 h after LTP induction was also shown. We hypothesize that those changes in NMDAR composition could be involved in the ''anti-amnesic effect'' of the previous OF. Along certain time interval, an increase in GluN1 and GluN2A would lead to an increase in synaptic NMDARs, facilitating synaptic plasticity and memory; while then, an increase in GluN2A/GluN2B ratio could protect the synapse and the already established plasticity, perhaps saving the specific trace.
Neurochemical Research, 2005
Male Wistar rats received bilateral infusions of vehicle (VEH) or aminophosphonopentanoic acid (AP5), an N-metil-D-aspartate (NMDA) receptor antagonist, into the dorsal hippocampus immediately after inhibitory avoidance (IA) training. Intrahippocampal infusion of AP5 blocked 24 h IA retention. In the second experiment, animals were preexposed to the IA training context 24 h prior to training and received an infusion of either VEH or AP5 immediately after the preexposure trial and a second infusion of VEH or AP5 immediately after IA training. AP5 did not affect retention in animals preexposed to the IA box and given VEH after preexposure, but blocked retention when given after both preexposure and training. AP5 impaired retention in rats preexposed to an environment distinct from the IA box. These results suggest that NMDA receptors in the dorsal hippocampus mediate the formation of a contextual representation of the task environment.
Journal of Neural Transmission, 1999
The role of ventral hippocampus glutamate receptors on learning mechanisms and memory was studied in the rat. Adult male rats were unilaterally implanted in the ventral hippocampus with microinjection cannulas. The general experimental procedure used was the chemical stimulation of hippocampal neurons with glutamic acid alone or in combination with glutamate receptor antagonists during learning of an active avoidance response. The one-way active response consisted in avoiding an electric shock applied to the feet while an ultrasonic tone of 40 KHz was on. Two series of experiments were performed. In Experiment 1, the possible effect of glutamate on the evocation of the learned avoidance response was studied. In Experiment 2, the possible effect of glutamate on the acquisition of the avoidance response was analyzed. Experiment 1 showed that glutamate in the range 1-10 nmol did not interfere with the recall of the avoidance response, suggesting that glutamate has no effect on the hippocampal evocation processes. Experiment 2 showed that glutamic acid inhibits the acquisition process, increasing the latency time of escape and deteriorating the learning efficiency. This effect was antagonized by AP7, the NMDA-glutamate receptor antagonist, and increased by AP3, the metabotropic glutamate receptor antagonist. Present data suggest that metabotropic glutamate receptors facilitate and NMDA-glutamate receptors inhibit the learning hippocampal mechanisms in the rat.
Behavioural Brain Research, 2000
Extensive evidence suggests that N-methyl-D-aspartate (NMDA) glutamate receptor channels in the amygdala are involved in fear-motivated learning, and infusion of NMDA receptor antagonists into the amygdala blocks memory of fear-motivated tasks. Recent studies have shown that previous training can prevent the amnestic effects of NMDA receptor antagonists on spatial learning. In the present study, we evaluated whether infusion of the NMDA antagonist D,L-2-amino-5-phosphonopentanoic acid (AP5) into the basolateral nucleus of the amygdala (BLA) impairs reinforcement of inhibitory avoidance learning in rats given previous training. Adult male Wistar rats (220-310 g) were bilaterally implanted under thionembutal anesthesia (30 mg/kg, i.p.) with 9.0-mm guide cannulae aimed 1.0 mm above the BLA. Infusion of AP5 (5.0 mg) 10 min prior to training in a step-down inhibitory avoidance task (0.4 mA footshock) blocked retention measured 24 h after training. When infused 10 min prior to a second training session in animals given previous training (0.2 mA footshock), AP5 blocked the enhancement of retention induced by the second training. Control experiments showed that the effects were not due to alterations in motor activity or footshock sensitivity. The results suggest that NMDA receptors in the basolateral amygdala are involved in both formation of memory for inhibitory avoidance and enhancement of retention in rats given previous training.
Molecular Brain Research, 2000
. It is widely accepted that the formation of long-term memory LTM requires neuronal gene expression, protein synthesis and the remodeling of synaptic contacts. From mollusk to mammals, the cAMPrPKArCREB signaling pathway has been shown to play a pivotal role in the establishment of LTM. More recently, the MAPK cascade has been also involved in memory processing. Here, we provide evidence for the participation of hippocampal PKArCREB and MAPKrElk-1 pathways, via activation of NMDA receptors, in memory formation of a one-trial avoidance learning in rats. Learning of this task is associated with an activation of p44 and p42 MAPKs, CREB and Elk-1, along with an increase in the levels of the catalytic subunit of PKA and Fos protein in nuclear-enriched hippocampal fractions. These changes were blocked by the immediate posttraining intra-hippocampal infusion of APV, a selective blocker of glutamate NMDA receptors, which renders the animals amnesic for this task. Moreover, no changes were found in control-shocked animals. Thus, inhibitory avoidance training in the rat is associated with an increase in the protein product of an IEG, c-fos, which occurs concomitantly with the activation of nuclear MAPK, CREB and Elk-1. NMDA receptors appear to be a necessary upstream step for the activation of these intracellular cascades during learning. q
The role of NMDA receptors of the medial septum and dorsal hippocampus on memory acquisition
Pharmacology Biochemistry and Behavior, 2016
The glutamatergic neurons in the medial septal/diagonal band of broca (MS/DB) affect the hippocampal functions by modulating the septo-hippocampal neurons. Our study investigated the possible role of NMDA receptors of the medial septum nucleus (MS) and dorsal hippocampus (CA1) on memory acquisition in male Wistar rats. Animals were bilaterally implanted with chronic cannulae in the MS and CA1. Rats were trained in a step-through type inhibitory avoidance task, and tested 24 h after training to measure step-through latency as memory retrieval. Our results indicated that pre-training intra-MS or intra-CA1 infusions of NMDA (0.125 µg/rat) and D-AP7 (0.012 µ g/rat) increased and decreased memory acquisition, respectively when compared to saline control group. Also, pre-training intra-CA1 and intra-MS injection of an effect dose of D-AP7 (0.012 µg/rat) along with an effect dose of NMDA (0.125 µ g/rat) impaired memory acquisition. Interestingly, pre-training intra-CA1/MS infusion of D-AP7 (0.012 µg/rat) diminished memory response produced by pre-training injection of NMDA (0.125 µg/rat) in the MS/CA1, respectively (cross injection or bilateral injection). Also, all above doses of drugs did not alter locomotor activity. These results suggest that the glutamatergic pathway between the MS and CA1 regions is involved in memory acquisition process.
Roles of NMDA NR2B Subtype Receptor in Prefrontal Long-Term Potentiation and Contextual Fear Memory
Neuron, 2005
Cortical plasticity is thought to be important for the establishment, consolidation, and retrieval of permanent memory. Hippocampal long-term potentiation (LTP), a cellular mechanism of learning and memory, requires the activation of glutamate N-methyl-D-aspartate (NMDA) receptors. In particular, it has been suggested that NR2A-containing NMDA receptors are involved in LTP induction, whereas NR2B-containing receptors are involved in LTD induction in the hippocampus. However, LTP in the prefrontal cortex is less well characterized than in the hippocampus. Here we report that the activation of the NR2B and NR2A subunits of the NMDA receptor is critical for the induction of cingulate LTP, regardless of the induction protocol. Furthermore, pharmacological or genetic blockade of the NR2B subunit in the cingulate cortex impaired the formation of early contextual fear memory. Our results demonstrate that the NR2B subunit of the NMDA receptor in the prefrontal cortex is critically involved in both LTP and contextual memory. Neuron 860 References Arrigoni, E., and Greene, R.W. (2004). Schaffer collateral and perforant path inputs activate different subtypes of NMDA receptors on the same CA1 pyramidal cell. Br. J. Pharmacol. 142, 317-322. Artola, A., Brocher, S., and Singer, W. (1990). Different voltagedependent thresholds for inducing long-term depression and longterm potentiation in slices of rat visual cortex. Nature 347, 69-72. Auberson, Y.P., Allgeier, H., Bischoff, S., Lingenhoehl, K., Moretti, R., and Schmutz, M. (2002). 5-Phosphonomethylquinoxalinediones as competitive NMDA receptor antagonists with a preference for the human 1A/2A, rather than 1A/2B receptor composition. Bioorg. Med. Chem. Lett. 12, 1099-1102. Bast, T., Zhang, W.N., and Feldon, J. (2003). Dorsal hippocampus and classical fear conditioning to tone and context in rats: effects of local NMDA-receptor blockade and stimulation. Hippocampus 13, 657-675. Bear, M.F., and Kirkwood, A. (1993). Neocortical long-term potentiation. Curr. Opin. Neurobiol. 3, 197-202. Bi, G.Q., and Poo, M.M. (1998). Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type. J. Neurosci. 18, 10464-10472. Bliss, T.V., and Collingridge, G.L. (1993). A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31-39. Cassell, M.D., and Wright, D.J. (1986). Topography of projections from the medial prefrontal cortex to the amygdala in the rat. Brain Res. Bull. 17, 321-333.
Bulletin of Experimental Biology and Medicine, 2016
Activity of NMDA receptors is a prerequisite for numerous but not all forms of neuronal plasticity and learning. The present study examined the role of NMDA receptors in standard, weak, and repeated passive avoidance training in young chicks. Injection of MK-801, an antagonist of NMDA receptor, prior to strong training episode impaired subsequent memory recall. Moreover, repeated training did not restore the lost memory. In the double weak training protocol, the impairing effect of MK-801 was observed only when it was injected prior to the second but not to the fi rst training episode. These results suggest that activation of NMDA receptors is not a necessary stage for memory acquisition in the weak training task. In contrast, the mechanisms of strong training depending on activation of NMDA receptors can be probably involved into the second training episode performed against the background of existing NMDA receptor-independent memory about the fi rst training episode.
The difference in the amounts of NR2 subunits contained in NMDA receptors of the hippocampus has been related to their different involvement in activity-dependent synaptic plasticity. Here, we show that Ro 25-6981, a high-affinity and selective blocker of NMDA receptors containing NR2B subunits, is able to block the acquisition of a trace conditioning paradigm in adult rats, a task that requires the active participation of hippocampal circuits. Reconditioning with the same trace paradigm was also prevented by Ro 25-6981. In addition, we show that the slope of monosynaptic field excitatory postsynaptic potentials evoked at the dentate gyrus by single pulses presented to the medial perforant pathway increases significantly across conditioning sessions and during reconditioning, in a linear relationship with the increase in the number of classically conditioned eyelid responses. Administration of Ro 25-6981 prevented these learning-related changes in synaptic strength at the perforant pathway-dentate granule cell synapse. The present results suggest the involvement of NR2B-containing NMDA receptors in hippocampal functions related to both associative learning and activity-dependent synaptic plasticity.