Long-term potentiation: 50 years on: past, present and future.

We introduce and summarize reviews and research papers by speakers at a discussion meeting on 'Long-term potentiation: 50 years on' held at the Royal Society, London, on 20-21 November 2023. The meeting followed earlier discussion meetings marking the 30th and 40th anniversaries of the discovery of long-term potentiation. These new contributions give an overview of current research and controversies in a vibrant branch of neuroscience with important implications for our understanding of the neurobiological basis of many forms of learning and memory and a wide spectrum of neurological and cognitive disorders.This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Bacteriostatic effect of sequential hydrodynamic and ultrasound-induced stress.

AIMS: To elucidate the mechanism of action of a nonchemical microbial control technology employing coupled hydrodynamic and ultrasound-induced stress. METHODS & RESULTS: The effects of a laboratory model system using a commercial nonchemical device on Pseudomonas putida revealed growth and respiration were inhibited without a loss of viability from the treated population. Damage to cell membranes was evident using fluorescent microscopy and a reporter strain containing lux genes fused with a membrane damage stress-response promoter. Other reporter strains also indicated the possible involvement of DNA and protein repair systems. A consequence of treatment was a reduced ability to form biofilms. CONCLUSIONS: The nonchemical device caused a biostatic effect on treated cells induced by sublethal damage to several cellular systems, including cell membranes. SIGNIFICANCE AND IMPACT OF THE STUDY: The study demonstrates that biostasis can be an effective mechanism for microbial control in some industrial systems and provides insight into understanding and applying this device and other nonchemical microbial control technologies to real-world problems of microbial contamination.

Transsynaptic expression of a presynaptic glutamate receptor during hippocampal long-term potentiation.

Repetitive activation of excitatory synapses in the hippocampus produces a persistent enhancement of synaptic efficiency known as long-term potentiation (LTP). In anesthetized and in freely moving rats, the induction of LTP in the perforant path led to a transient increase in the amount of messenger RNA (mRNA) coding for a presynaptic glutamate receptor (GR33) in dentate granule cells. The amount of GR33 mRNA was increased for at least 5 hours after the induction of LTP but was indistinguishable from control values 1 day after induction. The N-methyl-D-aspartate receptor antagonist 2-aminophosphonovalerate prevented the induction of both LTP and the increase in GR33 mRNA. The amount of GR33 protein was increased in the mossy fiber terminal zone of dentate granule cells 5 hours after the induction of LTP. These results suggest that the induction of LTP in synapses at one stage in a neural network may lead to modification in synaptic function at the next stage in the network.

A Review of Magnetic Particle Imaging and Perspectives on Neuroimaging.

Magnetic particle imaging is an emerging tomographic technique with the potential for simultaneous high-resolution, high-sensitivity, and real-time imaging. Magnetic particle imaging is based on the unique behavior of superparamagnetic iron oxide nanoparticles modeled by the Langevin theory, with the ability to track and quantify nanoparticle concentrations without tissue background noise. It is a promising new imaging technique for multiple applications, including vascular and perfusion imaging, oncology imaging, cell tracking, inflammation imaging, and trauma imaging. In particular, many neuroimaging applications may be enabled and enhanced with magnetic particle imaging. In this review, we will provide an overview of magnetic particle imaging principles and implementation, current applications, promising neuroimaging applications, and practical considerations.

Single synaptic events evoke NMDA receptor-mediated release of calcium from internal stores in hippocampal dendritic spines.

We have used confocal microscopy to monitor synaptically evoked Ca2+ transients in the dendritic spines of hippocampal pyramidal cells. Individual spines respond to single afferent stimuli (<0.1 Hz) with Ca2+ transients or failures, reflecting the probability of transmitter release at the activated synapse. Both AMPA and NMDA glutamate receptor antagonists block the synaptically evoked Ca2+ transients; the block by AMPA antagonists is relieved by low Mg2+. The Ca2+ transients are mainly due to the release of calcium from internal stores, since they are abolished by antagonists of calcium-induced calcium release (CICR); CICR antagonists, however, do not depress spine Ca2+ transients generated by backpropagating action potentials. These results have implications for synaptic plasticity, since they show that synaptic stimulation can activate NMDA receptors, evoking substantial Ca2+ release from the internal stores in spines without inducing long-term potentiation (LTP) or depression (LTD).

Spatial and temporal changes in signal transduction pathways during LTP.

Following LTP induction in freely moving rats, in situ hybridization revealed discrete changes in the expression of one isoform in each of four families of serine/threonine kinases constitutively expressed in the dentate gyrus of the hippocampus. Expression of the alpha isoform of CaMKII showed a transient increase over the soma and a more persistent increase over the dendritic field of dentate granule cells. Of the PKC isoforms, only gamma PKC was up-regulated substantially 2 hr after LTP induction, declining to control levels 48 hr later. An increase in the expression of mRNA for ERK2 and raf-B was seen at 24 hr only. These results show that, during the maintenance phase of LTP in the hippocampus, there are selective increases in the expression of serine/threonine kinases and that these increases have specific and characteristic temporal and spatial profiles.

The suppression of long-term potentiation in rat hippocampus by inhibitors of nitric oxide synthase is temperature and age dependent.

At room temperature (23 degrees C-25 degrees C), the induction of long-term potentiation (LTP) in area CA1 of slices from young male Sprague-Dawley rats was depressed by preincubation with the nitric oxide synthase inhibitors NG-nitro-L-arginine (L-NA, 100 microM) and NG-nitro-L-arginine methyl ester (L-NAME, 100 microM). The D isomers were ineffective under the same conditions. Hemoglobin (20 microM) reduced but did not completely block LTP. Neither L-NA (at concentrations up to 1 mM) nor hemoglobin (20 microM) had any significant effect on LTP in slices from adult rats at room temperature, or in young rats at 29 degrees C-30 degrees C. These results suggest that nitric oxide is unlikely to play a role in the induction of LTP under physiological conditions.

Differential expression of immediate early genes in the hippocampus and spinal cord.

We have demonstrated that immediate early genes can be differentially activated within the central nervous system. We examined the effects of tetanic stimulation in the hippocampus and of noxious sensory stimulation of the spinal cord on the expression of eight immediate early genes. Induction of long-term potentiation (LTP) in the dentate gyrus resulted in an increase in mRNA and protein for NGFI-A (also termed Zif/268, Egr-1, or Krox 24), and less consistently for jun-B mRNA. No increase was seen for c-fos, NGFI-B, c-jun, jun-D, SRF, or PC4 mRNAs. Blockade of the NMDA receptor prevented the induction of both LTP and NGFI-A mRNA in the dentate gyrus. However, commissural stimulation, which prevented the induction of LTP, resulted in bilateral activation of all the genes examined, including NGFI-A. No change was seen in animals trained in a water maze. These results suggest that no simple relationship exists between LTP, spatial learning, and immediate early gene induction. Stimulation of sensory fibers resulted in an increase in mRNA for NGFI-A, c-fos, SRF, NGFI-B, and c-jun in spinal cord neurons. Blockade of the NMDA receptor had no effect on immediate early gene induction in the spinal cord.

A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories.

The induction of long-term potentiation (LTP) in the dentate gyrus of the hippocampus is associated with a rapid and robust transcription of the immediate early gene Zif268. We used a mutant mouse with a targeted disruption of Zif268 to ask whether this gene, which encodes a zinc finger transcription factor, is required for the maintenance of late LTP and for the expression of long-term memory. We show that whereas mutant mice exhibit early LTP in the dentate gyrus, late LTP is absent when measured 24 and 48 hours after tetanus in the freely moving animal. In both spatial and non-spatial learning tasks, short-term memory remained intact, whereas performance was impaired in tests requiring long-term memory. Thus, Zif268 is essential for the transition from short- to long-term synaptic plasticity and for the expression of long-term memories.

Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice.

We investigated synaptic communication and plasticity in hippocampal slices from mice overexpressing mutated 695-amino-acid human amyloid precursor protein (APP695SWE), which show behavioral and histopathological abnormalities simulating Alzheimer's disease. Although aged APP transgenic mice exhibit normal fast synaptic transmission and short term plasticity, they are severely impaired in in-vitro and in-vivo long-term potentiation (LTP) in both the CA1 and dentate gyrus regions of the hippocampus. The LTP deficit was correlated with impaired performance in a spatial working memory task in aged transgenics. These deficits are accompanied by minimal or no loss of presynaptic or postsynaptic elementary structural elements in the hippocampus, suggesting that impairments in functional synaptic plasticity may underlie some of the cognitive deficits in these mice and, possibly, in Alzheimer's patients.

Long-term potentiation in mice lacking the neural cell adhesion molecule L1.

Genetic evidence indicates that cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) are critical for activity-dependent synapse formation at the neuromuscular junction in Drosophila and have also been implicated in synaptic remodelling during learning in Aplysia (see [1] for review). In mammals, a widely adopted model for the process of learning at the cellular level is long-term potentiation (LTP) in the hippocampal formation. Studies in vitro have shown that antibodies to the IgCAMs L1 and NCAM reduce LTP in CA1 neurons of rat hippocampus, suggesting a role for these molecules in the modulation of synaptic efficacy, perhaps by regulating synaptic remodelling [2]. A role for NCAM in LTP has been confirmed in mice lacking NCAM [3] (but see [4]), but similar studies have not been reported for L1. Here we examine LTP in the hippocampus of mice lacking L1 [5,6], using different experimental protocols in three different laboratories. In tests of LTP in vitro and in vivo we found no significant differences between mutant animals and controls. Thus, contrary to expectation, our data suggest that L1 function is not necessary for the establishment or maintenance of LTP in the hippocampus. Impaired performance in spatial learning exhibited by L1 mutants may therefore not be due to hippocampal dysfunction [6].

A functional genomics approach to the study of avian innate immunity.

A second-generation 4,959 element cDNA microarray has been created and evaluated for its potential use in examining the avian innate immune response. The elements in this array were obtained from EST libraries of stimulated avian PMNC-derived monocytes/macrophages and supplemented by genes of interest from several specific innate immune pathways. The elements are spotted in triplicate resulting in 14,877 total spots per slide. The avian innate immunity microarray (AIIM) contains 25 avian interleukin, chemokine, and cytokine elements. The array also contains elements for several innate immune pathways, including genes involved in the Toll-like receptor (TLR) pathway (including six of the currently known avian TLR receptors), avian interferon/antiviral response pathway genes, and genes involved in apoptosis, antigen presentation and the oxidative burst. The AIIM can be used to evaluate global gene expression patterns in a number of immunologically relevant tissues and in chickens, turkeys and ducks. The array has also been evaluated for its ability to monitor the avian immune response to both bacterial (avian pathogenic Escherichia coli) and viral (avian influenza) avian pathogens.

Plasticity in the human central nervous system.

Long-term potentiation (LTP) is a well-characterized form of synaptic plasticity that fulfils many of the criteria for a neural correlate of memory. LTP has been studied in a variety of animal models and, in rodents in particular, there is now a strong body of evidence demonstrating common underlying molecular mechanisms in LTP and memory. Results are beginning to emerge from studies of neural plasticity in humans. This review will summarize findings demonstrating that synaptic LTP can be induced in human CNS tissue and that rodent and human LTP probably share similar molecular mechanisms. We will also discuss the application of non-invasive stimulation techniques to awake human subjects to induce LTP-like long-lasting changes in localized neural activity. These techniques have potential therapeutic application in manipulating neural plasticity to treat a variety of conditions, including depression, Parkinson's disease, epilepsy and neuropathic pain.

Molecular mechanisms of long-term potentiation in the insular cortex in vivo.

We have investigated molecular mechanisms of synaptic plasticity in the pathway between two forebrain structures important for taste learning, the basolateral amygdala (BLA) and the insular cortex. We report here that in vivo long-term potentiation (LTP) induced by BLA stimulation requires functional NMDA receptors and is modulated by muscarinic acetylcholine receptors. In addition, LTP results in the activation of cortical extracellular regulated kinase 1/2 (ERK1/2) and is blocked by inhibitors of ERK1/2 activation. Previous findings demonstrated the involvement of the same molecular mechanisms in the same cortical area during novel taste learning. The results demonstrate that both synaptic and behavioral plasticity share common molecular mechanisms in the insular cortex.

ERKI/II regulation by the muscarinic acetylcholine receptors in neurons.

Muscarinic acetylcholine receptors (mAChRs) are known to be involved in learning and memory, but the molecular basis of their involvement is not well understood. The availability of new and specific biochemical tools has revealed a crucial role for the mitogen-activated protein kinase (MAPK) family in learning and memory. Here, we examine the link between mAChRs and MAPK in neurons. Using the MAPK kinase (MEK)-specific inhibitor PD98059, we first demonstrate a necessary role for active ERKI/II in long-term potentiation in vivo. Using phospho-specific antibodies that recognize the activated form of ERKI/II, we find that the level of ERKI/II activation in brain is regulated by mAChRs. Carbachol, a muscarinic agonist, induces prolonged activation of ERKI/II, without effect on the related kinase SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal protein kinase) in primary cortical cultures. ERKI/II activation is Src-dependent and partially phosphoinositide-3 kinase- and Ca(2+)-dependent but is PKC-independent. M1-M4 mAChR subtypes expressed in COS-7 cells can all induce ERKI/II activation using a signal transduction pathway similar to that operating in neurons. The nature of the signal transduction suggests that ERKI/II can serve as a convergence site for mAChR activation and other neurotransmitter receptors.

Protein phosphatase-1 regulation in the induction of long-term potentiation: heterogeneous molecular mechanisms.

Protein phosphatase inhibitor-1 (I-1) has been proposed as a regulatory element in the signal transduction cascade that couples postsynaptic calcium influx to long-term changes in synaptic strength. We have evaluated this model using mice lacking I-1. Recordings made in slices prepared from mutant animals and also in anesthetized mutant animals indicated that long-term potentiation (LTP) is deficient at perforant path-dentate granule cell synapses. In vitro, this deficit was restricted to synapses of the lateral perforant path. LTP at Schaffer collateral-CA1 pyramidal cell synapses remained normal. Thus, protein phosphatase-1-mediated regulation of NMDA receptor-dependent synaptic plasticity involves heterogeneous molecular mechanisms, in both different dendritic subregions and different neuronal subtypes. Examination of the performance of I-1 mutants in spatial learning tests indicated that intact LTP at lateral perforant path-granule cell synapses is either redundant or is not involved in this form of learning.

Eml5, a novel WD40 domain protein expressed in rat brain.

We have isolated a novel transcript with homology to the major microtubule-associated protein in dividing sea urchin embryos, EMAP. The protein has a predicted MW of approximately 180 kDa and we have named it Eml5 (EMAP-like protein 5). Eml5 contains 11 putative WD40 domains and 3 hydrophobic stretches of 43 aa, HELP domains, which have been suggested to be involved in microtubule binding. Eml5 appears to consist of two tandem repeats of the complete EMAP protein separated by a putative dimerization domain. Eml5 mRNA and protein is expressed at high levels in the hippocampus, cerebellum and olfactory bulb, as determined by in situ hybridization and immunocytochemistry. Eml5 transcripts can be detected in fore- and hindbrain structures from embryonic day 13 onwards. Because other EMAP-like proteins are involved in regulating microtubule dynamics, it is likely that Eml5 plays a role in the regulation of cytoskeletal rearrangements during neuronal development and in adult brain

Time-related Changes in Basal Phosphoinositide Turnover after Induction of Long-term Potentiation in the Dentate Gyrus are Blocked by Commissural Stimulation.

We have examined basal phosphoinositide turnover in synaptosomes obtained from the dentate gyrus of anaesthetized rats in which long-term potentiation was induced unilaterally in perforant path-granule cell synapses. Relative to the unpotentiated side, [3H]myo-inositol labelling of inositol phosphates was significantly enhanced 45 min and 3 h after induction of long-term potentiation, but reduced after 2.5 min. Similarly, [14C]arachidonic acid labelling of 1,2-diacylglycerol was increased 45 min and 3 h after induction of long-term potentiation, but reduced after 2.5 min. In a second series of experiments, induction of long-term potentiation was blocked by stimulation of the commissural projection to granule cells. In synaptosomes prepared from this tissue, there was no difference in phosphoinositide turnover between tetanized and control sides at any of the three post-tetanic intervals. We conclude that in the dentate gyrus, long-term potentiation is associated with an increase in phosphoinositide turnover which is established between 2.5 min and 45 min post-tetanus and which persists for at least 3 h.

Noradrenaline modulates the release of [14C]glutamate from dentate but not from CA1/CA3 slices of rat hippocampus.

The modulation of the release of [14C]glutamate by noradrenaline (NA) was investigated in slices prepared from the dentate gyrus and from the CA1/CA3 area of the hippocampus. In dentate, but not in CA1/CA3 slices, NA significantly enhanced K+-induced Ca2+-dependent release, and this effect was mimicked by clonidine and isoprenaline, but not by phenylephrine. The enhancement of release by NA was antagonised by propranolol, but not by yohimbine or phentolamine. These results suggest that NA does not modulate the release of glutamate in CA1/CA3, but does so in the dentate gyrus, probably by acting on presynaptically-located beta receptors.

Photolytic release of nitric oxide modulates NMDA receptor-mediated transmission but does not induce long-term potentiation at hippocampal synapses.

We have investigated the effects of photolytic release of nitric oxide (NO) on synaptic transmission in the hippocampal slice. Intracellular and extracellular recording techniques were used to monitor synaptic transmission in area CA1 of slices prepared from young rats and maintained in an interface chamber at 24 degrees C. N-methyl-D-aspartate (NMDA) receptor-mediated transmission was depressed, in a concentration- and haemoglobin-dependent manner, by NO released from perfusion fluid containing an inert photosensitive precursor, K2Ru(NO)Cl5, following exposure to a flash of near-UV light. However, conjunction of photolytic release of NO together with either weak high frequency stimulation, or strong stimulation in the presence of the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D(-)AP5), did not lead to a persistent enhancement of synaptic efficacy. These results establish that photolytically released NO can affect NMDA receptor-mediated transmission but do not support a role for NO as a retrograde messenger at CA1 synapses.