Studies Of Long-term Potentiation Research Articles

A review of plasticity induced by auditory and visual tetanic stimulation in humans.

Long-term potentiation is a form of synaptic plasticity thought to play an important role in learning and memory. Recently noninvasive methods have been developed to induce and measure activity similar to long-term potentiation in humans. Sensory tetani (trains of quickly repeating auditory or visual stimuli) alter the electroencephalogram in a manner similar to electrical stimulation that results in long-term potentiation. This review briefly covers the development of long-term potentiation research before focusing on in vivo human studies that produce long-term potentiation-like effects using auditory and visual stimulation. Similarities and differences between traditional (animal and brain tissue) long-term potentiation studies and human sensory tetanization studies will be discussed, as well as implications for perceptual learning. Although evidence for functional consequences of sensory tetanization remains scarce, studies involving clinical populations indicate that sensory induced plasticity paradigms may be developed into diagnostic and research tools in clinical settings. Individual differences in the effects of sensory tetanization are not well-understood and provide an interesting avenue for future research. Differences in effects found between research groups that have emerged as the field has progressed are also yet to be resolved.

Rapid increase in clusters of synaptophysin at onset of homosynaptic potentiation in Aplysia

Imaging studies have shown that even the earliest phases of long-term plasticity are accompanied by the rapid recruitment of synaptic components, which generally requires actin polymerization and may be one of the first steps in a program that can lead to the formation of new stable synapses during late-phase plasticity. However, most of those results come from studies of long-term potentiation in rodent hippocampus and might not generalize to other forms of synaptic plasticity or plasticity in other brain areas and species. For example, recruitment of presynaptic proteins during long-term facilitation by 5HT in Aplysia is delayed for several hours, suggesting that whereas activity-dependent forms of plasticity, such as long-term potentiation, involve rapid recruitment of presynaptic proteins, neuromodulatory forms of plasticity, such as facilitation by 5HT, involve more delayed recruitment. To begin to explore this hypothesis, we examined an activity-dependent form of plasticity, homosynaptic potentiation produced by tetanic stimulation of the presynaptic neuron in Aplysia. We found that homosynaptic potentiation involves presynaptic but not postsynaptic actin and a rapid (under 10 min) increase in the number of clusters of the presynaptic vesicle-associated protein synaptophysin. These results indicate that rapid recruitment of synaptic components is not limited to hippocampal potentiation and support the hypothesis that activity-dependent types of plasticity involve rapid recruitment of presynaptic proteins, whereas neuromodulatory types of plasticity involve more delayed recruitment.

Controlled in situ preparation of Aβ(1–42) oligomers from the isopeptide “iso-Aβ(1–42)”, physicochemical and biological characterization

β-Amyloid (Aβ) peptides play a crucial role in the pathology of the neurodegeneration in Alzheimer's disease (AD). Biological experiments (both in vitro and animal model studies of AD) require synthetic Aβ peptides of standard quality, aggregation grade, neurotoxicity and water solubility. The synthesis of Aβ peptides has been difficult, owing to their hydrophobic character, poor solubility and high tendency for aggregation. Recently an isopeptide precursor (iso-Aβ(1–42)) was synthesized by Fmoc-chemistry and transformed at neutral pH to Aβ(1–42) by O→ N acyl migration in a short period of time. We prepared the same precursor peptide using Boc-chemistry and studied the transformation to Aβ(1–42) by acyl migration. The peptide conformation and aggregation processes were studied by several methods (circular dichroism, atomic force and transmission electron microscopy, dynamic light scattering). The biological activity of the synthetic Aβ(1–42) was measured by ex vivo (long-term potentiation studies in rat hippocampal slices) and in vivo experiments (spatial learning of rats). It was proven that O→ N acyl migration of the precursor isopeptide results in a water soluble oligomeric mixture of neurotoxic Aβ(1–42). These oligomers are formed in situ just before the biological experiments and their aggregation grade could be standardized.

An alternate cAMP pathway Epac promotes hippocampal long‐term depression

The CA1 region of the hippocampus is a model system for the study of long-term synaptic plasticity, which is thought to play an important role in learning and memory. Specifically, studies of long-term potentiation (LTP) and long-term depression (LTD) have provided many insights into the molecular processes that govern long-term synaptic modifcations. While many signalling molecules have been implicated in the regulation of synaptic plasticity, the cyclic-adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) has proven to play a vital role (Nguyen & Woo, 2003). In particular, PKA enhances LTP through downstream phosphorylation events and gene regulation (Nguyen & Woo, 2003). Conversely, PKA activation inhibits LTD (Nguyen & Woo, 2003).

Coupled Phosphatase and Kinase Switches Produce the Tristability Required for Long-Term Potentiation and Long-Term Depression

Studies of long-term potentiation (LTP) and long-term depression (LTD) strongly suggest that individual synapses can be bidirectionally modified. A central question is the biochemical mechanisms that make LTP and LTD persistent. Previous theoretical models have proposed that the autophosphorylation properties of CaMKII could underlie a bistable molecular switch that maintains LTP, and there is experimental support for this mechanism. In contrast, there has been comparatively little theoretical or experimental work regarding the mechanisms that maintain LTD. Several lines of evidence indicate that LTD is not simply a reversal of previous LTP but rather involves separate biochemical reactions. These findings indicate that a minimal model of the synapse must involve a tristable system. Here, we describe a phosphatase (PP2A) switch, which together with a kinase switch form a tristable system. PP2A can be activated by a Ca(2+)-dependent process but can also be phosphorylated and inactivated by CaMKII. When dephosphorylated, PP2A can dephosphorylate itself. We show that these properties can lead to a persistent increase in PP2A during LTD (as reported experimentally), thus forming a phosphatase switch. We show that the coupled PP2A and CaMKII switches lead to a tristable system in which the kinase activity is high in the LTP state; the PP2A activity is high in the LTD state, and neither activity is high in the basal state. Our results provide an explanation for the recent finding that inhibition of PP2A prevents LTD induction.

Co-induction of long-term potentiation and long-term depression at a central synapse in the leech

Most studies of long-term potentiation (LTP) have focused on potentiation induced by the activation of postsynaptic NMDA receptors (NMDARs). However, it is now apparent that NMDAR-dependent signaling processes are not the only form of LTP operating in the brain [Malenka, R. C., & Bear, M. F. (2004). LTP and LTD: An embarrassment of riches. Neuron, 44, 5–21]. Previously, we have observed that LTP in leech central synapses made by the touch mechanosensory neurons onto the S interneuron was NMDAR-independent [Burrell, B. D., & Sahley, C. L. (2004). Multiple forms of long-term potentiation and long-term depression converge on a single interneuron in the leech CNS. Journal of Neuroscience, 24, 4011–4019]. Here we examine the cellular mechanisms mediating T-to-S (T→S) LTP and find that its induction requires activation of metabotropic glutamate receptors (mGluRs), voltage-dependent Ca2+ channels (VDCCs) and protein kinase C (PKC). Surprisingly, whenever LTP was pharmacologically inhibited, long-term depression (LTD) was observed at the tetanized synapse, indicating that LTP and LTD were activated at the same time in the same synaptic pathway. This co-induction of LTP and LTD likely plays an important role in activity-dependent regulation of synaptic transmission.

Memory consolidation of Pavlovian fear conditioning requires nitric oxide signaling in the lateral amygdala

Nitric oxide (NO) has been widely implicated in synaptic plasticity and memory formation. In studies of long-term potentiation (LTP), NO is thought to serve as a 'retrograde messenger' that contributes to presynaptic aspects of LTP expression. In this study, we examined the role of NO signaling in Pavlovian fear conditioning. We first show that neuronal nitric oxide synthase is localized in the lateral nucleus of the amygdala (LA), a critical site of plasticity in fear conditioning. We next show that NO signaling is required for LTP at thalamic inputs to the LA and for the long-term consolidation of auditory fear conditioning. Collectively, the findings suggest that NO signaling is an important component of memory formation of auditory fear conditioning, possibly as a retrograde signal that participates in presynaptic aspects of plasticity in the LA.

Integrins, synaptic plasticity and epileptogenesis.

A number of processes are thought to contribute to the development of epilepsy including enduring increases in excitatory synaptic transmission, changes in GABAergic inhibition, neuronal cell death and the development of aberrant innervation patterns in part arising from reactive axonal growth. Recent findings indicate that adhesion chemistries and, most particularly, activities of integrin class adhesion receptors play roles in each of these processes and thereby are likely to contribute significantly to the cell biology underlying epileptogenesis. As reviewed in this chapter, studies of long-term potentiation have shown that integrins are important for stabilizing activity-induced increases in synaptic strength and excitability. Other work has demonstrated that seizures, and in some instances subseizure neuronal activity, modulate the expression of integrins and their matrix ligands and the activities of proteases which regulate them both. These same adhesion proteins and proteases play critical roles in axonal growth and synaptogenesis including processes induced by seizure in adult brain. Together, these findings indicate that seizures activate integrin signaling and induce a turnover in adhesive contacts and that both processes contribute to lasting changes in circuit and synaptic function underlying epileptogenesis.

Field potential recordings in dentate gyrus of anesthetized rats: stability of baseline.

Urethane is a standard anesthetic utilized for in vivo recordings in the hippocampus. In studies of long-term potentiation (LTP), the measure of interest is the response amplitude minutes to hours following train delivery. In the absence of experimental treatment, we have consistently observed upward drift in the amplitude of the population spike (PS) and EPSP slope of the dentate gyrus (DG) evoked field response in acute surgical preparations performed in the urethanized rat. The present study systematically monitored PS amplitude and EPSP slope in the DG every 30 minutes for 6 hours following optimal positioning of Teflon-coated bipolar stainless steel electrodes under urethane anesthesia. At maximal stimulus intensities, large time-dependent increases in PS amplitude (70-80%) were observed over the first 2-4 hours, an effect that was exaggerated at lower stimulus intensities. Increases in the EPSP slope were smaller in magnitude (20-30%) and stabilized within a shorter period of time (1-2 hours). Animals were warmed on a heating pad and body and brain temperature remained constant over the recording session. Reducing stimulating electrode size and recording with glass micropipettes did not alleviate the upward drift in response amplitude. Similar increases were also seen under pentobarbital anesthesia. To dissociate anesthetic from surgical effects, recordings were obtained from animals previously prepared with indwelling electrodes and injected with urethane. Although slight declines (10-15%) in EPSP slope occurred over time, no significant alterations in PS amplitude were seen in the chronic preparation at high stimulus intensities. Low stimulus intensities yielded a more variable response pattern and, in direct contrast to the acute preparation, time-dependent declines, not increases, were noted in both parameters. These data suggest that generalized surgical trauma contributes to the upward drift in response amplitude and indicate that long stabilization periods are required in acute surgical preparations for accurate field potential recordings.

Studies of long-term potentiation and depression of inhibitory transmission by mathematical modeling of post-synaptic processes.

A mathematical model of posttetanic processes launched by rhythmic stimulation of the excitatory and inhibitory inputs to the dendritic spine of a pyramidal neuron in hippocampal field CA3 was used to study conditions for modifying the efficiency of the inhibitory input. The level of dephosphorylation of GABAa and GABAb receptors, which determines the GABA sensitivity of these receptors, was shown to depend on the Ca(2+)-dependent ratio of active protein kinases and protein phosphatases; the level of dephosphorylation decreased monotonically as the intracellular Ca2+ increased. Posttetanic increases and decreases in the Ca2+ concentration, as compared with the level achieved during the previous stimulation, led to increases or decreases respectively in the number of dephosphorylated GABA receptors and to induction of long-term potentiation and depression, respectively, in the efficiency of inhibitory transmission. The extent of the modification effect depended on the ratio of the quantities of inhibitory and excitatory mediators in the synaptic cleft. At very low or very high GABA concentrations, modification of inhibitory transmission was insignificant.

Chapter 2 Genetic analysis of NOS isoforms using nNOS and eNOS knockout animals

All three major isoforms of nitric oxide synthase (NOS) are expressed in the brain. Because of complex and overlapping expression patterns (Marletta, 1994; Nathan and Xie, 1994), the particular NOS isoform involved in many processes is not clear. In fact, NO generated by separate isoforms may have different roles and potentially opposing effects (Iadecola et al., 1994). We have taken a genetic approach, to disrupt or knockout the genes for NOS isoforms to circumvent some of the limitations of pharmacologic agents. This approach allows the study of each individual NOS isoform in physiologic processes in the context of intact animals. It gives insights into possible developmental roles for NO and parallel processes that may compensate for the absence of each NOS isoform. We have made nNOS and eNOS knockout mice, as well as double knockout mice that lack both nNOS and eNOS isoforms (Huang et al., 1993; Huang et al., 1995; Son et al., 1996). In this chapter, we review some of the physiologic roles for NO that have been elucidated making use of these mice, including regulation of cerebral blood flow, response to cerebral ischemia, regulation of neurotransmitter release in the brain, and development of synaptic plasticity. Other chapters will discuss results using NOS knockout animals in studies of long term potentiation (see Hawkins, this volume), neuronal development (see Mize, this volume), and potential mechanisms for protection in nNOS knockout mice (Moskowitz, M.A.; Dawson, V.L, this volume).

Brief theta-burst stimulation induces a transcription-dependent late phase of LTP requiring cAMP in area CA1 of the mouse hippocampus.

Memory storage in the mammalian brain can be divided into a short-term phase that is independent of new protein synthesis and a long-term phase that requires synthesis of new RNA and proteins. A cellular model for these two phases has emerged from studies of long-term potentiation (LTP) in the three major excitatory synaptic pathways in the hippocampus. One especially effective protocol for inducing robust and persistent LTP is "theta-burst" stimulation, which is designed to mimic the firing patterns of hippocampal neurons recorded during exploratory behavior in intact awake animals. Unlike LTP induced by non-theta tetanization regimens, little is known about the biochemical mechanisms underlying theta-burst LTP in the hippocampus. In the present study, we examined theta-burst LTP in the Schaffer collateral pathway. We found that 3 sec of theta-burst stimulation induced a robust and persistent potentiation (theta L-LTP) in mouse hippocampal slices. This theta L-LTP was dependent on NMDA receptor activation. The initial or early phase of theta-LTP did not require either protein or RNA synthesis and was independent of cAMP-dependent protein kinase (PKA) activation. In contrast, the late phase of theta-LTP required synthesis of proteins and RNA and was blocked by inhibitors of PKA. Prior induction of theta-LTP also occluded the potentiation elicited by chemical activation of PKA. Our results show that, like non-theta LTP, theta-induced LTP in area CA1 of the mouse hippocampus also involves transcription, translation, and PKA and suggest that cAMP-mediated gene transcription may be a common mechanism responsible for the late phases of LTP induced by both theta and non-theta patterns of stimulation.

Branching of active dendritic spines as a mechanism for controlling synaptic efficacy

Recent experimental findings [Yuste R. and Denk W. (1995) Nature 375, 682–684] suggest that dendritic spines possess excitable membranes. Theoretically, it was shown earlier that the shape of active spines can significantly affect somatopetal synaptic signal transfer. Studies of long-term potentiation in the hippocampus have related the increased synaptic efficacy to a number of structural modifications of spines, including an increased number of branched spines [Trommald M. et al. (1990) In Neurotoxicity of Excitatory Amino Acids, pp. 163–174. Raven Press, New York] and a strengthened capability for spines to alter their spatial positions [Hosokawa T. et al. (1995) J. Neurosci. 15, 5560–5573]. In the present simulation study, the potential physiological impact of several types of spine changes was examined in a compartmental neuron model built using the neuromodelling software NEURON [Hines M. (1993) In Neural Systems: Analysis and Modeling, pp. 127–136. Kluwer Academic, Norwell, MA]. The model included 30 complex spines, with dual component synaptic currents and mechanisms of Ca 2+ uptake, diffusion, binding and extrusion within spine heads. The results show that local clustering properties of spine distributions along dendrites are unlikely to affect synaptic efficacy. However, partial fusion of active spines, which results in formation of spine branches, or subtle changes in spine branch positions, could alone significantly increase synaptic signal transfer. These data illustrate possible mechanisms whereby subtle morphological changes in dendritic spines (compatible with changes reported in the literature) may be linked to the cellular mechanisms of learning and memory.

Chapter 27. Plasticity of excitatory synaptic transmission in the spinal cord dorsal horn

This chapter focuses on the recent information derived from experiments done in vitro using spinal slice preparation and acutely isolated spinal dorsal horn (DH) neurons of young rats. The emphasis is placed on modulation of synaptic and excitatory amino acids (EAAs) responses of DH neurons by κ-opioid receptor-preferring ligands and their potential role in long-term changes in synaptic transmission related to pain. To understand how opioids produce these changes, the cellular mechanisms of opioid actions have to be known. There is increasing evidence for involvement of opioids in long lasting activity-dependent changes in the efficacy of synaptic transmission in the brain and spinal cord. Studies of long-term potentiation (LTP) implicate opioid peptides in the induction of LTP in the hippocampus. In contrast, two reports suggest that dynorphin may reduce LTP in the hippocampus in a naloxone-reversible manner, at least in part, by a presynaptic action. Understanding the cellular mechanisms underlying the κ 1 -agonist actions has implications both for the understanding of somatosensory processing in the spinal DH and for the development of novel analgesic strategies to prevent post-injury pain hypersensitivity.

Complementary memory storage sites in mice: Their development as affected by the competitive NMDA receptor antagonist, CPP

Bitemporal injections of puromycin consistently induce amnesia of aversive maze learning in mice when administered within 3 days of training. These bitemporal puromycin injections lose their amnestic effectiveness if the latency between training and injection is extended beyond 6 days. Consistent with other evidence, we conclude that in our experimental paradigm, complementary memory storage sites normally develop in additional cerebral areas within 6 days following training. Previous experiments have indicated that the central adrenergic and cholinergic systems are critically involved in this process. We now present evidence that administration of the NMDA receptor antagonist, CPP, blocks the development of these complementary memory storage sites. As suggested by studies of long-term potentiation, NMDA receptor-dependent postsynaptic calcium appears to be essential for the development of these storage sites and indeed to trigger their development.

Studies of long-term potentiation in hippocampal slice with optical methods

Studies of long-term potentiation in hippocampal slice with optical methods

Studies of long-term potentiation in hippocampal slice with optical methods

Studies of long-term potentiation in hippocampal slice with optical methods

Long-term potentiation in the hippocampus

Long-term potentiation of field and single neuronal responses recorded in various hippocampal fields is described on the basis of author's and literary data. Most of intrahippocampal and extrinsic connections in both in vivo and in vitro hippocampal preparations show this phenomenon after one or several conditioning trains of comparatively short duration (20 s or less) at various frequencies (from 10 to 400 Hz). Properties of hippocampal potentiation are described. The properties include long term persistence (hours and days) of the potentiated response, its low frequency depression, self-restoration after the depression, specificity of the potentiation for the tetanized pathway, necessity of activation of a sufficient number of neuronal elements (‘cooperativity’) to produce the potentiation, possible involvement of ‘reinforcing’ brain structures during conditioning tetanization. These properties are distinct from those of ‘usual’ short-term post-tetanic potentiation and lead to the suggestion that the neuronal mechanisms underlying long-term potentiation are similar to those underlying memory and behavioralconditioned reflex. Neurophysiological mechanisms of long-term potentiation are discussed. The main mechanism consists in an increase in efficacy of excitatory synapses as shown by various methods including intracellular recording and quantal analysis. The latter favours presynaptic localization of the changes of synaptic efficacy showing increase in the number of transmitter quanta released per presynaptic impulse. However, changes in the number of subsynaptic receptors or localized changes in dendritic postsynaptic membrane are not excluded. Biochemical studies indicate the increase in transmitter release and calcium-dependent phosphorylation of pyruvate dehydrogenase after tetanization. Instances of persistent response facilitations at other levels of the vertebrate central nervous system (especially at neocortical level) are considered and compared with hippocampal long-term potentiation. It is suggested that modifiable excitatory synapses necessary for learning have been identified in studies of long-term potentiation. These synapses are presumably modified as a result of close sequential activation of the following three structures: excitatory presynaptic fibers, the postsynaptic neuron and a ‘reinforcing’ brain system.