Since its discovery by Bliss and Lomo, the phenomenon of long-term potentiation (LTP) has been extensively studied, as it was viewed as a potential cellular mechanism of learning and memory. Over the years, many signaling cascades have been implicated in its induction, consolidation and maintenance, raising questions regarding its real significance. Here, we review several of the most commonly studies signaling cascades and discuss how they converge on a common set of mechanisms likely to be involved in the maintenance of LTP. We further argue that the existence of cross-talks between these different signaling cascades can not only account for several discrepancies in the literature, but also account for the existence of different forms of LTP, which can be engaged by different types of stimulus parameters under different experimental conditions. Finally, we discuss how the understanding of the diversity of LTP mechanisms can help us understand the diversity of the types of learning and memory.

In 1973, two papers from Bliss and Lømo and from Bliss and Gardner-Medwin reported that high-frequency synaptic stimulation in the dentate gyrus of rabbits resulted in a long-lasting increase in synaptic strength. This form of synaptic plasticity, commonly referred to as long-term potentiation (LTP), was immediately considered as an attractive mechanism accounting for the ability of the brain to store information. In this historical piece looking back over the past 50 years, we discuss how these two landmark contributions directly motivated a colossal research effort and detail some of the resulting milestones that have shaped our evolving understanding of the molecular and cellular underpinnings of LTP. We highlight the main features of LTP, cover key experiments that defined its induction and expression mechanisms, and outline the evidence supporting a potential role of LTP in learning and memory. We also briefly explore some ramifications of LTP on network stability, consider current limitations of LTP as a model of associative memory, and entertain future research orientations.

Learning and memory are generally considered the behavioral correlates of long-term potentiation (LTP), a form of synaptic plasticity associated with a persistent and long-lasting increase in synaptic strength. Repetitive stimulation of excitatory synapses in the hippocampal CA1 region leads to release and binding of glutamate to the glutamate receptors AMPAR and NMDAR located on pyramidal neurons. Activation of AMPARs facilitates Na+ influx, postsynaptic depolarization, NMDAR-mediated Ca2+ influx, and activation of several intracellular mechanisms that characterize LTP, including increased AMPAR synthesis, ROS production, and ER Ca2+ release. BDNF-TrkB receptor signaling, which increases intracellular Ca2+ levels via PLCγ1-mediated ER Ca2+ release, also plays an important role in facilitating hippocampal CA1 LTP. Interestingly, the cellular mechanisms that characterize LTP are strikingly similar to signaling pathways that underlie reactivation of latent HIV-1 reservoirs. Known as the "shock and kill" approach, reactivation of latent HIV-1, particularly in CD4+ memory T cells, is currently being pursued to potentially eradicate HIV-1. Indeed, AMPARs, NMDARs, and TrkB receptors have been found on and promote T cell activation and BDNF has been shown to reactivate latent HIV-1 in human macrophages. Additionally, latent HIV-1 reactivation via T cell receptor activation (a positive control in HIV-1 latency studies) involves PLCγ1-mediated increases in intracellular Ca2+, an increase in ROS levels, and activation of kinases and transcription factors that are also critical for LTP. Furthermore, PMA, also used as a positive control along with ionomycin in HIV-1 latency studies, has been shown to enhance hippocampal CA1 LTP. AMPK, an evolutionarily conserved kinase activated by increases in intracellular Ca2+, ROS, and/or AMP/ATP ratio increases improves lifespan and healthspan in several model organisms and is essential for T cell activation. Knockdown of AMPK also significantly inhibits HIV-1 replication. AMPK has been found localized in hippocampal CA1 dendrites and glutamate, NMDA, KCl, ionomycin, and BDNF have each been shown to induce AMPK activation in neurons. AMPK activation also increases synthesis and membrane insertion of AMPARs. Because both T cell activation and LTP are dependent on intracellular Ca2+ increases and because inhibition of ROS significantly inhibits hippocampal CA1 LTP and T cell activation, it is our hypothesis that AMPK links latent HIV-1 reactivation with hippocampal LTP, learning, and memory. We also propose that compounds that enhance or promote LTP and reactivate latent HIV-1 (e.g. PMA, ionomycin, resveratrol, metformin, etc.) either alone or in combination likely do so via AMPK activation.

Alzheimer's disease (AD) is the most common type of dementia in which oxidative stress plays an important role. In this disease, learning and memory and the cellular mechanism associated with it, long‐term potentiation (LTP), are impaired. Considering the beneficial effects of carvacrol (CAR) and p‐cymene against AD, their effect was assessed on in vivo hippocampal LTP in the perforant pathway (PP)‐dentate gyrus (DG) pathway in an Aβ1‐42‐induced rat model of AD.

of cellular depolarization) leads to a rise in post-synaptic Ca2+ concentration and this has been linked to long-term potentiation, LTP (as well as to In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory (see Hebbian theory). The correlative Hebbian sy As the brain ages, many individuals experience a decline in memory and learning, which has been known to be linked to changes in synaptic plasticity. The hippocampus, the brain's main function for creating new memories, becomes implicated with age. Although this concept of neuronal communication weakening with age has been understood as the primary source for deficits in memory, researchers have recently been aiming to address what specific biological changes are responsible. One possible contributor to this is the regulation of the lGF-2 gene, which produces the protein lFG-2, a protein known to support memory and synaptic function. The gene lGF-2 is a gene that aids in synaptic plasticity in the hippocampus. In a study involving rats, researchers found a decrease in this gene due to methylation, a chemical tag that reduces gene activity. This decrease of lFG-2 was linked to poorer memory and weak long-term potentiation, a system involved in strengthening synapses. The researchers took it a step further and tested whether restoring the gene through a CRISPR-based method would increase the lFG-2 promoter by activating the DNA marks. In older rats, the treatment successfully improved both memory and synaptic function, suggesting that reversing these age-related changes could help restore synaptic activity in aging brains. Overall, this study shows the importance of gene activity in age-related memory deficits. When the lFG-2 gene becomes overly methylated with age, it causes synaptic plasticity in the hippocampus to weaken. By reversing this change, not only does memory performance improve, but the brain's ability to strengthen synapses becomes stronger.

MicroRNAs (miRNAs) have recently come to be viewed as critical players that modulate a number of cellular features in various biological systems including the mature CNS by exerting regulatory control over the stability and translation of mRNAs. Despite considerable evidence for the regulatory functions of miRNAs, the identities of the miRNA species that are involved in the regulation of synaptic transmission and plasticity and the mechanisms by which these miRNAs exert functional roles remain largely unknown. In the present study, the expression of microRNA-188 (miR-188) was found to be upregulated by the induction of long-term potentiation (LTP). The protein level of neuropilin-2 (Nrp-2), one of the possible molecular targets for miR-188, was decreased during LTP induction. We also confirmed that the luciferase activity of the 3′-UTR of Nrp-2 was diminished by treatment with a miR-188 oligonucleotide but not with a scrambled miRNA oligonucleotide. Nrp-2 serves as a receptor for semaphorin 3F, which is a negative regulator of spine development and synaptic structure. In addition, miR-188 specifically rescued the reduction in dendritic spine density induced by Nrp-2 expression in hippocampal neurons from rat primary culture. Furthermore, miR-188 counteracted the decrease in the miniature EPSC frequency induced by Nrp-2 expression in hippocampal neurons from rat primary culture. These findings suggest that miR-188 serves to fine-tune synaptic plasticity by regulating Nrp-2 exp

Yellow silk cocoons of Bombyx mori provide two distinct bioactive classes: the carotenoid silk lutein (SL) and sericin-derived oligopeptides (SDOs). Their comparative efficacy and mechanisms in promoting cognitive health remain uncharacterized. This study compared the neuroprotective and cognitive-enhancing effects of SL and SDOs through chronic oral administration in two rodent models: an amyloid-beta (A<i>β</i>_25-35)-induced amnesia model in mice and a natural aging model in rats. Cognitive function was assessed using the Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests, and underlying mechanisms were investigated via in vivo hippocampal long-term potentiation (LTP) and immunohistochemical analysis for apoptosis markers. Both SL and SDOs significantly ameliorated <i>Aβ</i>-induced deficits in recognition and spatial memory. Both substances enhanced spatial memory and LTP in old male rats in the natural aging paradigm, with efficacy comparable to that of donepezil (Don). This LTP-enhancing effect was sex-specific, being prominent in males but absent in aged females, although both sexes showed improved recognition memory. Critically, cognitive impairments in the <i>Aβ</i> model were not associated with significant neuronal apoptosis, and the protective effects appeared independent of anti-apoptotic pathways. In conclusion, SL and SDOs are potent cognitive-enhancing agents that mitigate memory deficits in acute neurotoxicity and chronic aging models. Their primary mechanism appears to be a robust enhancement of hippocampal synaptic plasticity rather than apoptosis prevention, positioning them as powerful synaptoprotective agents. These findings validate the potential to upcycle this agro-industrial byproduct into high-value nutraceuticals for promoting healthy brain aging.