Memory Storage In Mice Research Articles

Age-Dependent Changes in Synaptic NMDA Receptor Composition in Adult Human Cortical Neurons.

The molecular processes underlying the aging-related decline in cognitive performance and memory observed in humans are poorly understood. Studies in rodents have shown a decrease in N-methyl-D-aspartate receptors (NMDARs) that contain the GluN2B subunit in aging synapses, and this decrease is correlated with impaired memory functions. However, the age-dependent contribution of GluN2B-containing receptors to synaptic transmission in human cortical synapses has not been previously studied. We investigated the synaptic contribution of GluN2A and GluN2B-containing NMDARs in adult human neurons using fresh nonpathological temporal cortical tissue resected during neurosurgical procedures. The tissue we obtained fulfilled quality criteria by the absence of inflammation markers and proteomic degradation. We show an age-dependent decline in the NMDA/AMPA receptor ratio in adult human temporal cortical synapses. We demonstrate that GluN2B-containing NMDA receptors contribute to synaptic responses in the adult human brain with a reduced contribution in older individuals. With previous evidence demonstrating the critical role of synaptic GluN2B in regulating synaptic strength and memory storage in mice, this progressive reduction of GluN2B in the human brain during aging may underlie a molecular mechanism in the age-related decline in cognitive abilities and memory observed in humans.

The Neuralized-1 ubiquitin ligase regulates CPEB3-dependent protein synthesis of AMPA receptors in adult mammalian neurons and enhances synaptic plasticity and memory

Event Abstract Back to Event The Neuralized-1 ubiquitin ligase regulates CPEB3-dependent protein synthesis of AMPA receptors in adult mammalian neurons and enhances synaptic plasticity and memory Elias Pavlopoulos1*, Pierre Trifilieff1, Vivien Chevaleyre1, Sakellarios Zairis1, Gael Malleret2, Steven Soegelbaum1 and Eric Kandel1 1 Columbia University, United States 2 Universite Clasite Claude Bernard Lyon1, France Recent studies in Drosophila have delineated the Neuralized ubiquitin ligase as limiting for long-term memory formation. We now ask does this ligase have a similar role in hippocampal based memory storage in mice? We find that the mouse homologue of Drosophila neur gene, Neurl1, is present in the forebrain of the adult mouse, and is expressed at particularly high levels in the hippocampus. Neurl1 protein is predominantly localized in dendrites at post-synaptic sites and its level is increased by synaptic activity. To investigate the role of Neurl1 in memory, we generated mice that conditionally over-express Neurl1 in the forebrain and in particular with high levels of expression in the hippocampus. In these mice we find that over-expression of Neurl1 in the hippocampus significantly enhances hippocampal-dependent memory, as well as long-term potentiation in the Schaeffer-collateral pathway of acute adult hippocampal slices. This indicates that it is also a limiting factor for memory processes in mammals. In investigating how Neurl1 acts to enhance memory, we found that over-expression of Neurl1 results in increased number of functional synapses in the hippocampus as well as an overall increase in GluR1 and GluR2 subunits of AMPA receptors (AMPARs), both essential components in synaptic plasticity and memory. This increase in GluR1 and GluR2 was independent of transcription or recycling, suggesting a role of Neurl1 in the regulation of their translation. Indeed, we find that the GluR1 and GluR2 mRNAs are targets of and are controlled by a regulator of protein synthesis, the cytoplasmic polyadenylation element-binding protein 3 (CPEB3). Neurl1 over-expression results both in increased levels of CPEB3 and in up-regulation of CPEB3-dependent translation of AMPARs. These results suggest a model whereby Neuralized-1 facilitates hippocampal plasticity and hippocampal-dependent memory by modulating the levels of CPEB3 and of CPEB3-dependent synthesis of GluR1 and GluR2. Conference: 41st European Brain and Behaviour Society Meeting, Rhodes Island, Greece, 13 Sep - 18 Sep, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Pavlopoulos E, Trifilieff P, Chevaleyre V, Zairis S, Malleret G, Soegelbaum S and Kandel E (2009). The Neuralized-1 ubiquitin ligase regulates CPEB3-dependent protein synthesis of AMPA receptors in adult mammalian neurons and enhances synaptic plasticity and memory. Conference Abstract: 41st European Brain and Behaviour Society Meeting. doi: 10.3389/conf.neuro.08.2009.09.256 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: 12 Jun 2009; Published Online: 12 Jun 2009. * Correspondence: Elias Pavlopoulos, Columbia University, New York, United States, ep2185@columbia.edu 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 Elias Pavlopoulos Pierre Trifilieff Vivien Chevaleyre Sakellarios Zairis Gael Malleret Steven Soegelbaum Eric Kandel Google Elias Pavlopoulos Pierre Trifilieff Vivien Chevaleyre Sakellarios Zairis Gael Malleret Steven Soegelbaum Eric Kandel Google Scholar Elias Pavlopoulos Pierre Trifilieff Vivien Chevaleyre Sakellarios Zairis Gael Malleret Steven Soegelbaum Eric Kandel PubMed Elias Pavlopoulos Pierre Trifilieff Vivien Chevaleyre Sakellarios Zairis Gael Malleret Steven Soegelbaum Eric Kandel 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.

Inducible Enhancement of Memory Storage and Synaptic Plasticity in Transgenic Mice Expressing an Inhibitor of ATF4 (CREB-2) and C/EBP Proteins

To examine the role of C/EBP-related transcription factors in long-term synaptic plasticity and memory storage, we have used the tetracycline-regulated system and expressed in the forebrain of mice a broad dominant-negative inhibitor of C/EBP (EGFP-AZIP), which preferentially interacts with several inhibiting isoforms of C/EBP. EGFP-AZIP also reduces the expression of ATF4, a distant member of the C/EBP family of transcription factors that is homologous to the Aplysia memory suppressor gene ApCREB-2. Consistent with the removal of inhibitory constraints on transcription, we find an increase in the pattern of gene transcripts in the hippocampus of EGFP-AZIP transgenic mice and both a reversibly enhanced hippocampal-based spatial memory and LTP. These results suggest that several proteins within the C/EBP family including ATF4 (CREB-2) act to constrain long-term synaptic changes and memory formation. Relief of this inhibition lowers the threshold for hippocampal-dependent long-term synaptic potentiation and memory storage in mice.

Gabapentin, an antiepileptic drug, improves memory storage in mice

Male CF-1 mice were tested 48 h after training in a one-trial step-through inhibitory avoidance task. Immediately post-training i.p. injections of the antiepileptic drug gabapentin (1-aminomethyl cyclohexaneacetic acid) (GBP; 5, 10, 50, and 100 mg/kg) induced a dose-dependent enhancement of retention performance. Gabapentin did not affect response latencies in mice not given the footshock on the training trial, indicating that the actions of GBP on retention were not due to non-specific proactive effects on response latencies. The effects of GBP (10 mg/kg) were time-dependent, and the administration of GBP (10 mg/kg) 30 min before training also enhanced retention performance. However, the administration of GBP (10 mg/kg) 30 min prior to the retention test did not modify retention latencies of mice that had received either saline or GBP (10 mg/kg) immediately after training. Altogether, the results suggest that GBP influences retention by modulating time-dependent processes involved in memory storage, although the mechanism(s) of this action remain to be established.

Phlorizin, a Competitive Inhibitor of Glucose Transport, Facilitates Memory Storage in Mice

Posttraining intraperitoneal administration of phlorizin (3.0–300.0 μg/kg), a competitive inhibitor of glucose transport from blood to brain, facilitated 48-h retention, in male Swiss mice, of a one-trial step-through inhibitory avoidance task. The dose–response curve was an inverted-U shape. Phlorizin did not increase the retention latencies of mice that had not received a foot shock during training. The effects of phlorizin (30.0 μg/kg) on retention were time dependent, and the administration of phlorizin (30.0 μg/kg) 5 or 10 min prior to the retention test did not affect the retention performance of mice given posttraining injections of saline or phlorizin (30.0 μg/kg). These findings indicate that phlorizin influenced memory storage, but not memory retrieval. Finally, the simultaneous administration of phlorizin (3.0–300.0 μg/kg, ip) antagonized, in a dose-related manner, the memory impairment induced by insulin (8 IU/kg, ip). Taken together, the results show that phlorizin enhance retention acting as a “glucose-like substance” although the mechanism(s) of this enhancement is unknown.

Effects of a Single Administration of Oxytocin or Vasopressin and Their Interactions with Two Selective Receptor Antagonists on Memory Storage in Mice

The neuropeptides arginine vasopressin (AVP) and oxytocin (OT) have been thought to play a significant role in behavioral regulation in general and in learning and memory in particular. Experimental evidence suggests that AVP improves, and OT impairs, learning and memory. The present paper investigates the posttraining effects of OT and of an OT receptor antagonist, and their interaction, on memory storage in mice. Additional studies were conducted to determine the specificity of the interaction between OT and its receptors. Male Swiss mice were tested 48 h after training in a one-trial step-through inhibitory avoidance task. Immediate posttraining subcutaneous injection of OT (0.01, 0.03, 0.10, 0.30, and 1.00 μg/kg) impaired retention performance. The dose–response curve showed a U-shaped form, with a significant impairment seen at doses of 0.10 and 0.30 μg/kg of OT. In contrast, the immediate posttraining administration of the putative oxytocin receptor antagonistd(CH2)5[Tyr(Me)2, Thr4, Thy-NH92]OVT (AOT, 0.03, 0.10, 0.30, and 1.00 μg/kg) significantly enhanced retention performance. The dose–response curve was an inverted “U” in this range of doses. However, of the doses tested, only 0.30 μg/kg was effective. Neither OT nor AOT affected response latencies in mice not given the footshock on the training trial, indicating that the actions of both treatments on retention performance were not due to nonspecific proactive effects on response latencies. Neither the imparing effects of OT (0.10 μg/kg) nor the enhancing effects of AOT (0.30 μg/kg) were seen when the training–treatment interval was 180 min, suggesting that both treatments influenced the storage of recently acquired information. The effects of OT (0.10 μg/kg) on retention were prevented by AOT (0.03 μg/kg) administered immediately after training, but 10 min prior to oxytocin treatment. This dose of antagonist did not affect retention by itself, either under the standard experimental conditions or in mice trained with a lower level of footshock. On the contrary, OT (0.10 μg/kg) impaired retention in mice pretreated with the V1avasopressin receptor antagonistd(CH2)5[Tyr(Me)2]AVP (0.01 μg/kg), which, however, was able to prevent the enhancement of retention induced by posttraining administration of AVP (0.03 μg/kg). Finally, the effects of AVP (0.03 μg/kg) on retention were not prevented by AOT (0.03 μg/kg). Considered together, these findings suggest that the impairment of retention of an inhibitory avoidance response in mice induced by posttraining oxytocin is probably due to an interaction of the neuropeptide with specific receptors.

A nitric oxide synthase inhibitor impairs memory storage in mice

Abstract Posttraining administration of the l -enantiomer of the competitive inhibitor of nitric oxide synthase, N G -nitro- l -arginine methyl ester ( l -NAME, 3–100 mg/kg, ip), impaired 48-h retention of a one-trial step-through inhibitory shock-avoidance task in male Swiss mice. The effects were dose-dependent and were not observed when the d -enantiomer ( d -NAME, 3–100 mg/kg, ip) was injected instead of l -NAME. Retention latencies of mice that had not received a footshock during training were not affected by l -NAME. The memory impairment produced by l -NAME was time-dependent, suggesting an action on memory storage. The effects of l -NAME on memory were overcome by the injection of l -(but not d -)arginine (300 mg/kg, ip) along with the inhibitor. Considered together, these findings suggest that the l -arginine/nitric oxide pathway may be involved in memory storage of an inhibitory avoidance response in mice.

Post-training minaprine enhances memory storage in mice: involvement of D1 and D2 dopamine receptors.

Post-training administration of minaprine (2.5, 5 and 10 mg/kg) dose-dependently improved retention of an inhibitory avoidance response in mice. Animals receiving nine daily injections of 5 mg/kg and administered a challenge dose post-training showed an improvement in memory consolidation similar to that produced by acute injection of 10 mg/kg. The effects on retention performance induced by the drug appear to be due to an effect on memory consolidation. They were observed when drugs were given at short, but not long, periods of time after training, i.e. when the memory trace was susceptible to modulation. Moreover, these effects are not to be ascribed to an aversive or a rewarding or non-specific action of the drugs on retention performance, as the latencies during the retention test of those mice that had not received a footshock during training were not affected by post-training drug administration. The effects of an acutely injected dose (10 mg/kg) of minaprine as well as those of a challenge dose (5 mg/kg) of the drug administered to repeatedly treated animals were reversed by pretreatment with either selective D1 or D2 dopamine receptor antagonists SCH 23390 and (-)-sulpiride administered at per se non-effective doses (0.025 and 6 mg/kg, respectively), thus suggesting that D1 and D2 receptor types are similarly involved in the effects of minaprine on memory consolidation. These results show that minaprine improves memory consolidation and that repeated drug administration leads to potentiation of this effect. Moreover, the effects of minaprine on memory consolidation are related to its dopaminergic action.

Strain-dependent effects of post-training dopamine receptor agonists and antagonists on memory storage in mice

Post-training administration of the selective D1 or D2 agonists SKF 38393 and LY 171555 dose dependently impairs retention of an inhibitory avoidance response in DBA/2 mice. In agreement, the selective D1 or D2 antagonists SCH 23390 and (-)-sulpiride improve retention. These effects are opposite to those observed in the C57BL/6 strain, as previously reported. Moreover, B6D2F1 hybrids present a response to SKF 38393, LY 171555, SCH 23390, and (-)-sulpiride that parallels that of the C57BL/6 strain, thus suggesting that the neural mechanisms underlying the effects of DA agonists or antagonists on memory processes may be inherited through a dominant mode of inheritance.

Post-training dopamine receptor agonists and antagonists affect memory storage in mice irrespective of their selectivity for D1 or D2 receptors

Post-training administration of the selective D1 and D2 agonists SKF 38393 and LY 171555 dose-dependently facilitated retention of an inhibitory avoidance response in mice, while the selective D1 or D2 antagonists SCH 23390 and (-)sulpiride produced an impairment of retention. These effects are not to be ascribed to a nonspecific action of the drugs on retention performance, as the latencies during the retention test of those mice that had not received a footshock during the training were not increased by the post-training drug administration. The effects on retention performance induced by DA agonists and antagonists seem to be due to an effect on memory consolidation, since they have been observed when drugs were given at short, but not at long, periods of time after training. These results showing a similar role of D1 and D2 receptor types on memory storage appear not to be consistent with a body of neuropharmacological, neurophysiological, and behavioral evidence pointing to a different functional role of these types of DA receptors. This discrepancy is discussed in terms of possible involvement of different brain systems, peripheral systems, or possible second messenger processes activated by the two receptor types and leading to similar effects on memory processes.

Cocaine enhances memory storage in mice.

Mice were trained on a one-trial inhibitory avoidance task and given immediate post-training intraperitoneal injections of cocaine (0.03-1.00 mg/kg). On a retention test 24 h later, the retention latencies of mice given the 0.10 mg/kg dose were significantly higher than those of the controls. The effect of cocaine on retention was time-dependent: retention latencies were not altered in animals given cocaine 60 min after training. Administration of cocaine (0.1 mg/kg) prior to the retention test did not modify the retention performance of mice that received either saline or cocaine (0.1 mg/kg) immediately post-training. The findings suggest that cocaine affects retention by influencing post-training processes involved in memory storage.

Effects of pentylenetetrazol on memory storage in mice.

This paper reports several studies of the effects of pentylenetetrazol on learning in mice. The first three studies indicated that, for several strains and learning tasks, the degree of facilitation produced by posttrial injections of subconvulsive doses of pentylenetetrazol varied with the different strains and experimental conditions used. The fourth experiment showed that facilitation of learning is obtained only when the drug is injected within 15 minutes before or after training. Other findings indicated that the convulsive and lethal doses of pentylenetetrazol depend upon the animals' deprivation state and that when given to rats in subconvulsive doses, the drug produces EEG effects which are seen within minutes after injection and which last for less than one hour. We interpret the results of these learning experiments as indicating that pentylenetetrazol enhances learning by affecting processes involved in memory storage.