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William H Ridder III,1 Reena Patel,1 Yong-Xin Li,2 Ursula Staubli2 1Southern California College of Optometry, Marshall B. Ketchum University, Fullerton, CA, USA; 2AbbVie, Inc, Irvine, CA, USACorrespondence: William H Ridder III, Southern California College of Optometry, Marshall B. Ketchum University, 2575 Yorba Linda Blvd, Fullerton, CA, 92831, USA, Email wridder@ketchum.eduPurpose: Perceptual learning or dichoptic training may result in improved acuity in adult amblyopes. However, for amblyopic children (< 18 years), most clinicians recommend standard part-time patching. The purpose of this study was to determine if standard amblyopia therapy results in an enhancement in vision in the amblyopic eye of adults.Patients and Methods: Fifteen amblyopes (20/30 or worse) were recruited and nine (age (SD) 32.9 (16.31)) with anisometropia or anisometropia and strabismus (ie, combined mechanism amblyopia) completed the study. Previous therapy did not exclude subjects. The subjects received a comprehensive eye exam and wore their best correction for at least four weeks prior to baseline testing. The non-amblyopic eye was patched for 2 hours per day (Amblyopia iNET training for 30 minutes and near/distance activities for 1.5 hours). The subjects had a baseline amblyopia evaluation followed by one visit per week for 12 weeks. At 12 weeks, the treatment was tapered off over one month and the subjects had a final amblyopia evaluation at 24 weeks. Contrast sensitivity was measured at baseline and 12 weeks with the Quick CSF system.Results: The subjects had a significant improvement in visual acuity across the weeks (p < 0.001). At baseline, weeks 12 and 24, the average logMAR acuities (SE) were 0.55 (0.09), 0.41 (0.08), and 0.38 (0.09), respectively. Weeks 4 to 24 were significantly different (p < 0.001) from baseline. The average acuity improvement over the 24 weeks was 1.7 logMAR lines. There was a significant increase in the area under the log contrast sensitivity function (p = 0.002) and its estimated acuity (p = 0.036) from baseline to 12 weeks.Conclusion: Standard amblyopia treatment can result in an improvement in visual acuity and contrast sensitivity in adults with longstanding anisometropic or combined mechanism amblyopia even if they had prior therapy.Keywords: amblyopia, anisometropia, strabismus, contrast sensitivity, visual acuity

A benzamide drug that crosses the blood-brain barrier and facilitates DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic responses was tested for its effects on memory in three behavioral tasks. The compound reversibly increased the amplitude and prolonged the duration of field excitatory postsynaptic potentials in hippocampal slices and produced comparable effects in the dentgate gyrus in situ after intraperitoneal injections. Rats injected with the drug 30 min prior to being given a suboptimal number of training trials in a two-odor discrimination task were more likely than controls to select the correct odor in a retention test carried out 96 hr later. Evidence for improved memory was also obtained in a water maze task in which rats were given only four trials to find a submerged platform in the presence of spatial cues; animals injected with the drug 30 min before the training session were significantly faster than vehicle-injected controls in returning to the platform location when tested 24 hr after training. Finally, the drug produced positive effects in a radial maze test of short-term memory. Well trained rats were allowed to retrieve rewards from four arms of an eight-arm maze and then tested for reentry errors 8 hr later. The number of such errors was substantially reduced on days in which the animals were injected with the drug before initial learning. These results indicate that a drug that facilitates glutamatergic transmission enhances the encoding of memory across tasks involving different sensory cues and performance requirements. This may reflect an action on the cellular mechanisms responsible for producing synaptic changes since facilitation of AMPA receptors promotes the induction of the long-term potentiation effect.

The effect of hippocampal denervation on olfactory memory in rats was tested after interrupting the lateral olfactory tract projections at the level of the entorhinal cortex. When lesioned animals were trained to learn new odors, they showed no evidence of retention 3 h after acquisition. These results confirm earlier data on rapid forgetting in rats after hippocampal deafferentation and are in parallel to the anterograde amnesia typically found in humans with hippocampal damage. On the other hand, preoperatively learned information was minimally impaired after hippocampal deafferentation even if it was acquired within less than 1 h before the lesion. This finding differs from reports on humans as well as monkeys with hippocampal damage where memories formed during a critical time span of months or even years before the lesion are found to be impaired. This may suggest that the consolidation process in humans and rodents has different time scales or that the roles of the human and the rat hippocampal structure in memory formation are somewhat different.

The N -methyl-d-aspartate receptor coagonist d-serine is a substrate for the neutral amino acid transporters ASCT1 and ASCT2, which may regulate its extracellular levels in the central nervous system (CNS). We tested inhibitors of ASCT1 and ASCT2 for their effects in rodent models of schizophrenia and visual dysfunction, which had previously been shown to be responsive to d-serine. L-4-fluorophenylglycine (L-4FPG), L-4-hydroxyPG (L-4OHPG), and L-4-chloroPG (L-4ClPG) all showed high plasma bioavailability when administered systemically to rats and mice. L-4FPG showed good brain penetration with brain/plasma ratios of 0.7-1.4; however, values for L-4OHPG and L-4ClPG were lower. Systemically administered L-4FPG potently reduced amphetamine-induced hyperlocomotion in mice, whereas L-4OHPG was 100-fold less effective and L-4ClPG inactive at the doses tested. L-4FPG and L-4OHPG did not impair visual acuity in naive rats, and acute systemic administration of L-4FPG significantly improved the deficit in contrast sensitivity in blue light-treated rats caused by retinal degeneration. The ability of L-4FPG to penetrate the brain makes this compound a useful tool to further evaluate the function of ASCT1 and ASCT2 transporters in the CNS., (Copyright © 2018 by The Author(s).)

The N-methyl-d-aspartate receptor (NMDA) co-agonist d-serine is a substrate for the neutral amino acid transporters ASCT1 (SLC1A4) and ASCT2 (SLC1A5). We identified l-phenylglycine (PG) and its analogs as inhibitors of ASCT1 and ASCT2. PG analogs were shown to be non-substrate inhibitors of ASCT1 and ASCT2 with a range of activities relative to other amino acid transport systems, including sodium-dependent glutamate transporters, the sodium-independent d-serine transporter asc-1 and system L. L-4-chloroPG was the most potent and selective ASCT1/2 inhibitor identified. The PG analogs facilitated theta-burst induced long-term potentiation in rat visual cortex slices in a manner that was dependent on extracellular d-serine. For structurally-related PG analogs, there was an excellent correlation between ASCT1/2 transport inhibition and enhancement of LTP which was not the case for inhibition of asc-1 or system L. The ability of PG analogs to enhance LTP is likely due to inhibition of d-serine transport by ASCT1/2, leading to elevated extracellular levels of d-serine and increased NMDA receptor activity. These results suggest that ASCT1/2 may play an important role in regulating extracellular d-serine and NMDA receptor-mediated physiological effects and that ASCT1/2 inhibitors have the potential for therapeutic benefit., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The NMDA subtype of glutamate receptor and its co-agonist d-serine play a key role in synaptic function in the central nervous system (CNS), including visual cortex and retina. In retinal diseases such as glaucoma and macular degeneration, a loss of vision arises from malfunction of retinal cells, resulting in a glutamate hypofunctional state along the visual pathway in the affected parts of the visual field. An effective strategy to remedy this loss of function might be to increase extracellular levels of d-serine and thereby boost synaptic NMDA receptor-mediated visual transmission and/or plasticity to compensate for the impairment. We tested this idea in brain slices of visual cortex exhibiting long-term potentiation, and in rodent models of visual dysfunction caused by retinal insults at a time when the injury had stabilized to look for neuroenhancement effects. An essential aspect of the in vivo studies involved adapting sweep VEP technology to conscious rats and rabbits and combining it with intracortical recording while the animals were actively attending to visual information. Using this technology allowed us to establish complete contrast sensitivity function curves. We found that systemic d-serine dose-dependently rescued the contrast sensitivity impairment in rats with blue light-induced visual dysfunction. In rabbits with inner retinal dysfunction, both systemic and intravitreal routes of d-serine provided a rescue of visual function. In sum, we show that co-agonist stimulation of the NMDA receptor via administration of exogenous d-serine might be an effective therapeutic strategy to enhance visual performance and compensate for the loss of vision resulting from retinal disease., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

N-methyl-D-aspartate (NMDA) receptors play critical roles in synaptic transmission and plasticity. Activation of NMDA receptors by synaptically released L-glutamate also requires occupancy of co-agonist binding sites in the tetrameric receptor by either glycine or D-serine. Although D-serine appears to be the predominant co-agonist at synaptic NMDA receptors, the transport mechanisms involved in D-serine homeostasis in brain are poorly understood. In this work we show that the SLC1 amino acid transporter family members SLC1A4 (ASCT1) and SLC1A5 (ASCT2) mediate homo- and hetero-exchange of D-serine with physiologically relevant kinetic parameters. In addition, the selectivity profile of D-serine uptake in cultured rat hippocampal astrocytes is consistent with uptake mediated by both ASCT1 and ASCT2. Together these data suggest that SLC1A4 (ASCT1) may represent an important route of Na-dependent D-serine flux in the brain that has the ability to regulate extracellular D-serine and thereby NMDA receptor activity.

The enantiomers of erythro-3-hydroxyaspartate were tested for activity at glutamate transporters and NMDA receptors. Both enantiomers inhibited glutamate transporters in rat hippocampal crude synaptosomes and elicited substrate-like activity at excitatory amino acid transporter 1, 2, and 3 as measured by voltage clamp in the Xenopus oocyte expression system. The enantiomers had similar affinities, but the D-enantiomer showed a lower maximal effect at excitatory amino acid transporter 1, 2, and 3 than the L-enantiomer. Surprisingly, D-erythro-3-hydroxyaspartate was a potent NMDA receptor agonist with an EC 50 value in rat hippocampal neurons of 320 nM, whereas the L-enantiomer was 100-fold less potent. L-erythro-3-hydroxyaspartate showed activity at both glutamate transporters and NMDA receptors at concentrations that are reported to inhibit serine racemase, indicating a lack of selectivity. This enantiomeric pair may assist in shedding further light on the structural requirements for substrate activity at glutamate transporters and for agonist activity at NMDA receptors. The erythro enantiomers of 3-hydroxyaspartate had interesting and surprising effects on glutamate neurotransmitter systems. L-erythro-3-hydroxyaspartate had activity at both glutamate transporters (EAAT1/2/3) and NMDA receptors. D-erythro-3-hydroxyaspartate acted on EAATs, but was also identified as a highly potent NMDA receptor agonist. These enantiomers shed further light on the structural requirements for activity at EAATs and NMDA receptors., (© 2015 International Society for Neurochemistry.)

Understanding the storage and release of the excitatory neurotransmitter, L-glutamate by synaptic vesicles has lagged behind receptor characterizations due to a lack of pharmacological agents. We report that the glutamate analog, 3-aminoglutarate (3-AG) is a "silent" false transmitter for glutamate neurons that may be a useful tool to study storage and release mechanisms. Like L-glutamate itself, 3-AG is a high-affinity substrate for both the plasma membrane (EAATs) and vesicular (vGLUT) glutamate transporters. As such, EAATs facilitate 3-AG entry into neuronal cytoplasm allowing 3-AG to compete with L-glutamate for transport into vesicles thus reducing glutamate content. In a synaptosomal preparation, 3-AG inhibited calcium-dependent endogenous L-glutamate release. Unlike L-glutamate, 3-AG had low affinity for both ionotropic (NMDA and AMPA) and G-protein coupled (mGlu1-8) receptors. Consequently, 3-AG behaves as a "silent" false transmitter that may be used in physiological experiments to probe synaptic vesicle storage and release mechanisms for L-glutamate. The companion paper by Wu et al. (2015) describes initial experiments that explore the effects of 3-AG on glutamate synaptic transmission under physiological and pathophysiological conditions., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Pharmacological tools that interact with the mechanisms that regulate vesicular filling and release of the neurotransmitter L-glutamate would be of enormous value. In this study, we provide physiological evidence that the glutamate analog, 3-aminoglutarate (3-AG), acts as a false transmitter to reduce presynaptic glutamate release. 3-AG inhibits glutamate-mediated neurotransmission both in primary neuronal cultures and in brain slices with more intact neural circuits. When assayed with the low affinity glutamate receptor antagonist γ-DGG, we demonstrate that 3-AG significantly reduces the synaptic cleft glutamate concentration, suggesting that 3-AG may act as a false transmitter to compete with glutamate during vesicle filling. Furthermore, using three different epileptic models (Mg(2+)-free, 4-AP, and high K(+)), we demonstrate that 3-AG is capable of suppressing epileptiform activity both before and after its induction. Our studies, along with those of the companion paper by Foster et al. (2015) indicate that 3-AG is a "silent" false transmitter for glutamate neurons that is a useful pharmacological tool to probe the mechanisms governing vesicular storage and release of glutamate under both physiological and pathophysiological conditions. 3-AG may have potential therapeutic value in conditions where the glutamate neurotransmitter system is pathologically overactive., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Long-term potentiation (LTP) is a cellular model for persistent synaptic plasticity in the mammalian brain. Like several forms of memory, long-lasting LTP requires cAMP-mediated activation of protein kinase A (PKA) and is dependent on gene transcription. Consequently, activity-dependent genes such as c-fos that contain cAMP response elements (CREs) in their 5' regulatory region have been studied intensely. More recently, arg3.1/arc became of interest, because after synaptic stimulation, arg3.1/arc mRNA is rapidly induced and distributed to dendritic processes and may be locally translated there to facilitate synapse-specific modifications. However, to date nothing is known about the signaling mechanisms involved in the induction of this gene. Here we report that arg3.1/arc is robustly induced with LTP stimulation even at intensities that are not sufficient to activate c-fos expression. Unlike c-fos, the 5' regulatory region of arg3.1/arc does not contain a CRE consensus sequence and arg3.1/arc is unresponsive to cAMP in NIH3T3 and Neuro2a cells. However, in PC12 cells and primary cultures of hippocampal neurons, arg3.1/arc can be induced by cAMP and calcium. This induction requires the activity of PKA and mitogen-activated protein kinase, suggesting a neuron-specific pathway for the activation of arg3.1/arc expression.

Investigations of hippocampal theta cell activity have typically involved behavioral tasks with modest cognitive demands. Recordings in rats locomoting through space or engaged in simple stimulus discrimination or conditioning have revealed some place specificity and S(+)/S(-) selectivity in addition to the hippocampal EEG theta-related behavioral/motor correlates. However, little data exist regarding theta cell activity during performance of more cognitively demanding, hippocampal-dependent recognition memory tasks. Here, we examined the cognitive firing correlates of theta cells in rats that were performing an olfactory recognition memory task with distinct sample and test phases. Discriminant analysis revealed odor and match/nonmatch memory correlates in theta cell activity comparable in relative magnitude to that of the principal cells. Odor-specific theta cell responses in the sample phase were restricted primarily to CA1 and linked to task performance. In the test recognition phase, match/nonmatch theta cells were found primarily in the CA3 and CA1 fields, most of which exhibited greater activity on correct nonmatch trials in which recognition occurred than on error match trials in which recognition failed. Odor selectivity of the match/nonmatch signaling was greatest in the dentate gyrus (DG) and CA3 and least in CA1. This inverted pattern of stimulus specificity in the sample versus test phase was similar to that observed in principal cells but with a greater contrast between the CA1 and DG/CA3 fields. Together, these findings suggest that theta cells actively participate in hippocampal recognition memory processing and play a specific role in shaping the cognitive firing properties of the hippocampal principal cells.

In order to stabilize changes in synaptic strength, neurons activate a program of gene expression that results in alterations of their molecular composition and structure. Here we demonstrate that Fnk and Snk, two members of the polo family of cell cycle associated kinases, are co-opted by the brain to serve in this program. Stimuli that produce synaptic plasticity, including those that evoke long-term potentiation (LTP), dramatically increase levels of both kinase mRNAs. Induced Fnk and Snk proteins are targeted to the dendrites of activated neurons, suggesting that they mediate phosphorylation of proteins in this compartment. Moreover, a conserved C-terminal domain in these kinases is shown to interact specifically with Cib, a Ca(2+)- and integrin-binding protein. Together, these studies suggest a novel signal transduction mechanism in the stabilization of long-term synaptic plasticity.

In animals and several cellular models of synaptic plasticity, long-lasting changes in synaptic strength are dependent on gene transcription and translation. Here we demonstrate that Pim-1, a serine/threonine kinase closely related to Pim-2 and Pim-3, is induced in hippocampus in response to stimuli that evoke long-term potentiation (LTP). Mice deficient for Pim-1 show normal synaptic transmission and short-term plasticity. However, they fail to consolidate enduring LTP even though Pim-2 and Pim-3 are constitutively expressed in the hippocampus and Pim-3 expression is similarly induced by synaptic activity. Thus, expression of Pim-1 is required for LTP. Its level of expression and, consequently, its capacity to phosphorylate target proteins in dendritic and nuclear compartments of stimulated neurons might be a determining factor for the establishment of long-lasting changes in synaptic strength.

Homosynaptic long-term depression (LTD) is reported to occur in field CA1 of hippocampal slices collected from immature brains. Because the effect has been postulated to be a memory storage mechanism, it is of interest to test for its presence in adult, awake animals. Unfortunately, not only has hippocampal LTD proved difficult to obtain reliably in vivo, but the few successful studies vary with respect to protocols and evidence that the depression is input-specific. The present study tested for input-specific (homosynaptic) LTD in field CA1 after application of various stimulation protocols to the Schaffer collateral/commissural projections in freely moving, adult rats. The results indicate that although low-frequency trains do induce decrements in synaptic transmission lasting for hours to several days, the success rate of eliciting input-specific LTD in the awake rat is very modest compared with the ease with which stable potentiation is obtained in the same synapses. Moreover, it is questionable that the effective protocols represent patterns of activity likely to occur during behavior. The stronger the afferent activation during low-frequency stimulation, the greater was the probability of eliciting LTD accompanied by persistent heterosynaptic depression. Clear evidence for the occurrence of LTD, irrespective of stimulation protocol and current intensity, could not be obtained in rats under barbiturate anesthesia. In all, the results do not accord with the suggestion that LTD occurs routinely in the hippocampus in vivo as part of memory encoding.

Peptides known to block the extracellular interactions of adhesion receptors belonging to a subclass of the integrin family were tested for their effects on the stabilization of long-term potentiation (LTP) in hippocampal slices. Theta burst stimulation delivered after infusions of Gly-Ala-Val-Ser-Thr-Ala (GAVSTA) resulted in a potentiation effect that decayed steadily over a period of 40 min; LTP elicited in the presence of inactive control peptides remained stable over this time period. GAVSTA had no detectible influence on baseline responses, induction processes, or the initial degree of potentiation. Infusions of integrin antagonists after application of theta bursts also resulted in the occurrence of a decremental form of LTP. Affinity chromatography was then used in an effort to identify targets of the structurally dissimilar integrin blockers that disrupt LTP stabilization. Both integrin antagonists Gly-Arg-Gly-Asp-Ser-Pro and GAVSTA eluted a major species of 55 kDa (synaptegrin-1) from GRGDSP-affinity columns that had been loaded with solubilized synaptic membranes; lesser concentrations of three polypeptides of approximately 20, 27, and 30 kDa were also collected. Synaptegrin-1 was labeled by antibodies to the RGDS-binding integrin alpha5beta1. In addition, the synaptegrin, as well as the 27 kDa, protein was found to copurify with pre- and postsynaptic markers during the isolation of forebrain synaptosomes. These results indicate that a matrix recognition event occurring several minutes after induction of LTP is a necessary step in the stabilization of potentiated synapses; they also identify an integrin-like matrix receptor of 55 kDa that may contribute to this event.

The induction of long-term depression (LTD) was investigated in area CA1 of hippocampal slices from adult rats. To produce LTD, prolonged low-frequency stimulation (LFS, 900 stimuli at 1 Hz) was delivered to one of two independent Schaffer-collateral/commissural projections, while the second input served as a control to monitor heterosynaptic effects. The depression was calculated as percent decrease in the slope of the dendritic field EPSP relative to baseline values, and LTD was considered established if the response decrement was at least 15% in magnitude and stable for 30-60 min. By delivering LFS in conditions of different relative baseline response magnitudes, it was revealed that the intensity of afferent low-frequency activity has a significant impact on the induction frequency, magnitude and input-specificity of the depression: the rate of LTD occurrence and the effect of LFS on the absolute response decrement increased successively as the stimulation strength was raised, but the impact of LFS on the relative LTD magnitude decreased at higher stimulation intensities; the depression was specific to the stimulated input (homosynaptic LTD) when baseline responses were spike-free, but spread to the pathway which was silent during LFS (heterosynaptic LTD) in experiments conducted above spiking threshold. The results indicate that in the adult rat (i) the induction of input-specific LTD is dependent on the level of synaptic activation during LFS, and (ii) LTD can easily be obtained in strongly stimulated pathways but may be the result of a generalized decrease in the postsynaptic response.

A recently developed benzamide compound which facilitates glutamate receptor-mediated synaptic responses was used to test behavioral consequences of enhanced glutamatergic transmission. The drug was found to depress exploratory activity by rats in a novel environment. At a dose below threshold for causing such effects, drug-treated and control rats exhibited no evident behavioral differences during the acquisition phase of a radial maze experiment. Yet, when tested 2.5 h later, experimental animals were more likely than controls to choose maze arms that had not been entered during the acquisition session, suggesting that the drug enhanced retention of information about prior choices and the maze environment.

This chapter is concerned with the unexpected finding that the hippocampus contains two qualitatively different forms of long-lasting potentiation. High-frequency stimulation of the mossy fiber input to CA3 produces an increase in the size of evoked excitatory postsynaptic potentials (EPSPs) that in many respects resembles the long-term potentiation (LTP) effect in CA1. However, work by Harris and Cotman and by Zalutsky and Nicoll showed that mossy fiber potentiation is not induced by the same processes that trigger LTP. Experiments by this author have revealed that the two phenomena are based on different expression mechanisms: mossy fiber potentiation is associated with a decrease in paired-pulse facilitation indicating that its expression involves presynaptic changes; and LTP in the Schaffer-commisural projections does not affect paired-pulse facilitation or any of several other manipulations that increase release, suggesting that it is expressed by postsynaptic modifications. Direct evidence for the above conclusions has been obtained using aniracetam, a drug which selectively enhances currents mediated by the AMPA (quisqualate) receptors. As expected from its action on receptors, field EPSPs are increased by aniracetam; this effect is proportionally smaller following induction of LTP, but not after mossy fiber potentiation. These findings support the hypothesis that LTP reflects a change in the properties of AMPA receptors. In summary, the effects of presynaptic treatments are reduced by mossy fiber potentiation but not by LTP while a postsynaptic treatment is affected by LTP but not by mossy fiber potentiation. The above results point to the conclusion that mossy fiber potentiation is unlike LTP both in induction and expression mechanisms and thus is a wholly different form of synaptic plasticity.

The hypothesis that long-term potentiation (LTP) involves receptor modifications was tested with aniracetam, a nootropic drug that selectively increases currents mediated by the AMPA subclass of glutamate receptors. Aniracetam had different effects on the waveform of synaptic potentials in hippocampus before and after induction of LTP: (1) the drug caused a slight reduction (or delay) of the initial segment of the response after LTP; and (2) the facilitatory effects of aniracetam occurred at a later time point in the response after LTP than before. The interactions between LTP and aniracetam were still present when synaptic responses were greatly reduced by partial blockade of postsynaptic receptors and were not reproduced by increasing release or the number of stimulated synapses. A mathematical treatment of synaptic currents produced the following results: (1) if aniracetam facilitates AMPA receptor currents simply by reducing desensitization, then its complex interaction with LTP emerges when potentiation changes the kinetic and conductance properties of receptor channels; (2) if aniracetam also significantly increases conductance, then the experimental data can be reproduced by modeling LTP as an increase in channel conductance alone.

Aniracetam reversibly increased synaptic responses mediated by the AMPA but not the NMDA subclass of glutamate receptors in hippocampus and was considerably more potent than structurally similar nootropics. The drug had greater effects on field excitatory postsynaptic potentials (EPSPs) in the dentate gyrus and CA1 region than it did in the CA3 region, suggesting that it differentiates between variants of the AMPA receptor. Ligand binding to glutamate receptors in synaptosomal membrane fractions was minimally changed by aniracetam. Finally, the percent facilitation produced by aniracetam in the CA1 region was not reduced by any of three treatments (4-aminopyridine, changes in extracellular calcium concentrations, paired-pulse stimulation) that affect release but, in accord with a previous report, was substantially decreased by long-term potentiation. These results support the conclusion that aniracetam selectively increases the conductance of a subgroup of synaptic AMPA receptors in hippocampus and suggest that receptor changes underlie the expression of long-term potentiation.

Slices of hippocampus were incubated with Arg-Gly-Asp (RGD) peptides known to block members of the integrin class of matrix receptors. Though the peptides caused no detectable difference in the amount of long-term potentiation (LTP) expressed in the CA1 field 1-2 min after induction with high frequency stimulation, they did produce a reversible, dose dependent decay of LTP over a period of 40 min. This effect was not obtained with various non-RGD control peptides. These results suggest that stabilization of LTP requires adhesive interactions via specific matrix recognition sites, whereas induction and expression do not.

Three experiments assessed the effect of entorhinal cortex lesions on olfactory learning and memory using a successive-cue olfactory discrimination paradigm. In contrast to the results of other studies that used a simultaneous-cue paradigm, lesions of the entorhinal cortex facilitated rats' acquisition of individual odor discrimination problems, with no impairment in memory for the individual odors across both short (24-hr) and long (65-day) retention intervals and despite limited training. When considered together with previous observations of facilitation or impairment in learning after damage to the hippocampal system, the present data suggest that the hippocampus is preferentially involved in encoding relations among multiple stimuli. By this account, facilitation of performance is due to an interaction between hippocampal system dysfunction and task conditions that hinder direct comparisons among cues.

Adult rats with two chronic stimulating electrodes in the Schaffer collateral/commissural system of the hippocampus and one recording electrode in the stratum radiatum (apical dendrites) of field CA1 were administered high-frequency stimulation (10 brief bursts at theta frequency) to produce long-term potentiation (LTP). 'Low frequency' stimulation (100 pulses at 1 Hz alone or followed by 250 pulses at 5 Hz) delivered 5-15 min later had no effect on LTP in 18% of the rats, caused a transient reversal in 18% of the group, but produced an apparent reversal of LTP for the remainder of a 1 h test session in 64% of the animals. LTP did not recover in animals tested 24 h later, at which point a second episode of high-frequency stimulation but without subsequent low-frequency stimulation was administered. This produced an LTP effect that persisted for a 1 h test session in 94% of the cases and that was still present in 86% of the animals tested 24 h later. Low-frequency stimulation applied prior to induction of LTP had no lasting effects on evoked responses not did it affect responses to a control stimulating electrode in those cases in which it reversed LTP. Possible implications of these results for hypotheses concerning the substrates of LTP and mechanisms of forgetting are discussed.

Electrical stimulation of the Schaffer-collateral axonal system under conditions which do not elicit detectable seizure activity causes an increase in the activity of ornithine decarboxylase (ODC), the rate limiting enzyme of polyamine synthesis, in the hippocampus, olfactory cortex, neocortex and olfactory bulb. The degree of ODC activation is dependent upon the stimulus parameters. The results support the hypothesis that neuronal activity regulates hippocampal polyamine concentrations.

The stability of long-term potentiation (LTP) elicited by a stimulation paradigm in which short high-frequency bursts of pulses were given in a 'theta' pattern (i.e. 5 bursts/s) was tested in a chronic recording study. Stimulation electrodes were implanted bilaterally in the Schaffer-commissural system while the recording electrode was placed in the apical dendritic field of the Ca1 zone of the hippocampus. Following 4 days of baseline testing, 'theta' stimulation was applied to one electrode for a total of 2 s (ten 30 ms bursts), after which testing was continued for 3 weeks or until the responses fell to below baseline levels. Data were collected from 25 animals and 3 types of results were obtained: (1) no LTP (n = 4), (2) LTP that decreased steadily from 24 h after high frequency stimulation onward (n = 4), and (3) LTP that was stable until recording was terminated or until the responses began a precipitous decrease to below baseline values (n = 17). The mean of the slopes of the curves relating degree of potentiation to days after 'theta' stimulation was less than 1%/day with a mean correlation coefficient of only 0.1 prior to the point at which the responses began their rapid decline. Control responses were unaffected by the induction of LTP in neighboring CA1 afferents and did not exhibit a reliable relationship with time. These results suggest that, for most rats, LTP elicited by theta pattern stimulation is stable until such time that stimulation-recording arrangements begin to deteriorate.(ABSTRACT TRUNCATED AT 250 WORDS)

Prompted by evidence pointing to a key role of the N-methyl-D-aspartate (NMDA) receptor system in the induction of long-term potentiation and possibly in the formation of some types of memory, we examined the effect of chronic intraventricular administration of D-amino-phosphono-valeric acid (AP5), a competitive NMDA receptor antagonist, on olfactory discrimination and avoidance learning. These two tasks were selected because they are affected to very different degrees by damage to the hippocampus and other telencephalic structures rich in NMDA receptors. Twenty rats previously trained to solve a series of discriminations between two simultaneously presented odors were infused with either 20 mM D-AP5 or saline (n = 10 per group) for 14 days. An important and unusual feature of the paradigm was that it permitted a comparison of drug effects on acquisition of new discriminations versus retention of old ones. Animals treated with AP5 made significantly more errors than did saline controls in acquiring discriminations between low-intensity odors presented with long intertrial intervals (ITIs). However, no deficit was observed when short ITIs (less than 2 min) or strong odors were used. Animals treated with AP5 had no difficulty in recognizing odors on which they were trained before administration of the drug. After exhaustion of the pumps, performance of the AP5 group was indistinguishable from that of the control group. One-way active avoidance learning was not affected by chronic infusion of AP5. Several possibilities are discussed that could account for the selective olfactory learning deficit.(ABSTRACT TRUNCATED AT 250 WORDS)

Experiments were designed to investigate the role of post-trial reinforcing and subreinforcing stimulation of the substantia nigra on memory processing. Thirty sec post-trial reinforcing stimulation (0.2 sec on/1.8 sec off) impaired learning of response suppression in a step-down task compared to control animals as well as to animals stimulated at subthreshold current level (i.e., at 25% of the current level shown to maintain optimal self-stimulation in previously performed self-stimulation sessions). In a second small-box passive avoidance experiment, i.e., the alcove-avoidance task, opposite results were attained: Subreinforcing stimulation attenuated learning whereas neither suprathreshold stimulated animals nor control animals showed impairment of learning. The conclusions drawn from these results are as follows: Post-trial stimulation of the substantia nigra interferes with memory processing. This attenuation of learning is obviously task-dependent and can additionally be influenced by the quality of the stimulation, i.e., whether it is reinforcing or not. Possible explanations to account for these task-dependent and quality of stimulation-dependent effects of post-trial substantia nigra stimulation are discussed.

The effects of post-trial injection of substance P (SP) into the lateral hypothalamus (LH) and the ventromedial hypothalamus (VMH) on passive avoidance learning was studied in rats. In the VMH, 50 ng and 500 ng SP influenced neither learning of a step-down avoidance nor of an alcove avoidance response. In contrast to these findings, 500 ng SP injected into the LH significantly enhanced retention of the alcove avoidance task. Similarly, in the step-down avoidance experiment, learning was strongly facilitated by posttrial injection of 50 ng as well as 500 ng SP into the LH. These results, together with our previous data showing amnesia with posttrial injection of SP into amygdala and substantia nigra, suggest that exogenously applied SP influences the activity of those brain regions shown to contain high densities of SP-positive nerve terminals. Interestingly, the effects of posttrial SP injection parallel the effects of post-trial electrical brain stimulation on passive avoidance learning. Hence, posttrial SP retroactively facilitates or impairs learning depending on where in the brain it is injected.