Long-Term Potentiation

During the induction of long-term potentiation (LTP) in hippocampal slices adenosine triphosphate (ATP) is secreted into the synaptic cleft, and a 48 kDa/50 kDa protein duplex becomes phosphorylated by extracellular ATP. All the criteria required as evidence that these two proteins serve as principal substrates of ecto-protein kinase activity on the surface of hippocampal pyramidal neurons have been fulfilled. This phosphorylation activity was detected on the surface of pyramidal neurons assayed after synaptogenesis, but not in immature neurons nor in glial cells. Addition to the extracellular medium of a monoclonal antibody termed mAb 1.9, directed to the catalytic domain of protein kinase C (PKC), inhibited selectively this surface protein phosphorylation activity and blocked the stabilization of LTP induced by high frequency stimulation (HFS) in hippocampal slices. This antibody did not interfere with routine synaptic transmission nor prevent the initial enhancement of synaptic responses observed during the 1-5 min period immediately after the application of HFS (the induction phase of LTP). However, the initial increase in the slope of excitatory postsynaptic potentials, as well as the elevated amplitude of the population spike induced by HFS, both declined gradually and returned to prestimulus values within 30-40 min after HFS was applied in the presence of mAb 1.9. A control antibody that binds to PKC but does not inhibit its activity had no effect on LTP. The selective inhibitory effects observed with mAb 1.9 provide the first direct evidence of a causal role for ecto-PK in the maintenance of stable LTP, an event implicated in the process of learning and the formation of memory in the brain.The long-term potentiation (LTP) of synaptic strength in hippocampal pyramidal neurons is a neurophysiological process iinplicated in the formation of memory traces in the brain (1, 2). While the initial chain of events that triggers this process is well-known, the mechanisms that determine the duration and stability of LTP have not yet been fully elucidated. Although it is generally accepted that the phosphorylation of proteins by several different kinases is involved in this stabilization, their exact localization and roles are still obscure (2, 3). Protein phosphorylation, a ubiquitous step in intracellular pathways that produce transient changes in neuronal activity, was found to serve also as a key mechanism of molecular adaptation in processes underlying the induction of longlasting alterations in synaptic function (for reviews, see ref. 4), including learning and memory formation (5-7). The first study that implicated protein phosphorylation in the process of learning (5) identified a synaptic phosphoprotein that was later shown to be a major neuronal substrate of protein kinase C (PKC), that plays a role in the maintenance-phase of LTP (8, 9). The specific PKC-isozyme involved in the maintenance of LTP was reported to be PKC C, a member of the atypical class (not stimulated by diacylglycerol or phorbol ...

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Surface protein phosphorylation by ecto-protein kinase is required for the maintenance of hippocampal long-term potentiation.

Chen

Wieraszko

Hogan

et al. 1996

“…Repeated, brief, high-frequency trains of stimuli applied to the Schaffer collateral pathway of the CAl region of the hippocampus produce a long-lasting synaptic potentiation (LTP; long-term potentiation) that lasts several hours and even days to weeks in the intact animal (1,2). LTP has recently been dissected into two components, an early transient component (E-LTP) that requires the influx of calcium into the postsynaptic cell through N-methyl-D-aspartate (NMDA) receptor channels and the subsequent activation of several serinethreonine and tyrosine kinases (2,3), and a later more persistent component (L-LTP) that requires new protein and RNA synthesis (4)(5)(6)(7)(8).…”

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confidence: 99%

D1/D5 receptor agonists induce a protein synthesis-dependent late potentiation in the CA1 region of the hippocampus.

Huang

Kandel

1995

507

366

Agonists of the dopamine D1/D5 receptors that are positively coupled to adenylyl cyclase specifically induce a slowly developing long-lasting potentiation of the field excitatory postsynaptic potential in the CAl region ofthe hippocampus that lasts for >6 hr. This potentiation is blocked by the specific D1/D5 receptor antagonist SCH 23390 and is occluded by the potentiation induced by cAMP agonists. An agonist of the D2 receptor, which is negatively coupled to adenylyl cyclase through Gai, did not induce potentiation. Although this slow D1/D5 agonist-induced potentiation is partially independent of N-methyl-D-aspartate receptors, it seems to share some steps with and is occluded by the late phase of long-term potentiation (LTP) produced by three repeated trains of nerve stimuli applied to the Schaffer One modulatory system known to innervate the CAl region of the hippocampus is the mesolimbic dopaminergic pathway that ends on both the Dl and D5 dopaminergic receptors coupled to adenylyl cyclase (10, 11). Immunohistochemical localization of Dl and D5 receptors reveals a heavy staining along pyramidal cells and the stratum radiatum (12). Retrograde fluorescent tracers show that dopaminergic fibers that project from the ventral tegmental area innervate the CAl MATERIALS AND METHODSTransversely cut hippocampal slices (400 jim) were prepared from 5-to 6-week-old Sprague-Dawley rats and maintained in an interface chamber with continuous superfusion at 1.5-2 ml/min. The solution composition was 124 mM NaCl, 1.3 mM MgCl2, 4 mM KCl, 1.2 mM KH2PO4, 2.0-2.5 mM CaCl2, 25.6 mM NaHCO3, and 10 mM D-glucose, bubbled with 95% 02/5% CO2. The temperature of the bath was maintained at 28-29°C. After equilibration of the slices in the chamber for 2 hr, extracellular recordings were performed as described in a previous paper (7). Baseline responses were recorded for 30-60 min before drug application or LTP-inducing tetanization. Four biphasic constant current pulses (0.2 Hz; duration, 0.1-ms pulse) were used to generate test excitatory postsynaptic potentials (EPSPs) at 10-min intervals during the first hour after drug application or LTP induction and at 30-min intervals during the following hours. In LTP experiments an additional test was performed 1 min after tetanization to induce LTP. Three stimulus trains at 100 Hz, 1 s of 0.2-ms pulse duration were used, a tetanization protocol that produces long-lasting potentiation for up to 8 hr (6). The average waveform from four successive responses was saved and the EPSP slope (mV/ms) was measured.The following drugs were made and stored as concentrated stock solutions and dissolved in the superfusing medium to achieve the final concentrations used: D1/D5 agonist, SKF Abbreviations: LTP, long-term potentiation; E-LTP and L-LTP, early and late components of LTP; NMDA, N-methyl-D-aspartate; PKA, protein kinase A; EPSP, excitatory postsynaptic potential; APV, (±)-2-amino-5-phosphonopentanoic acid; PPHT, (±)-2-(N-phenylethyl-N-propyl)amino-5-hydroxytetralin hydrochloride; Sp-cAMPS, ad...

“…In addition to longevity, LTP is rapidly induced, strengthened by repetition, demonstrates specificity and associativity, and occurs prominently in the hippocampus, a structure implicated in learning and memory processes (14). Because of these properties, LTP is widely regarded as a potential synaptic mechanism underlying information storage (15,16). Other forms of stress, such as exposure to a novel environment, have been shown to block primed-burst potentiation (a low threshold form of LTP) in the hippocampus (17,18).…”

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confidence: 99%

Behavioral stress modifies hippocampal plasticity through N-methyl-D-aspartate receptor activation.

Kim

Foy

Thompson

1996

397

299

Behavioral stress has detrimental effects on subsequent cognitive performance in many species, including humans. For example, humans exposed to stressful situations typically exhibit marked deficits in various learning and memory tasks. However, the underlying neural mechanisms by which stress exerts its effects on learning and memory are unknown. We now report that in adult male rats, stress (i.e., restraint plus tailshock) impairs long-term potentiation (LTP) but enhances long-term depression (LTD) in the CAl area of the hippocampus, a structure implicated in learning and memory processes. These effects on LTP and LTD are prevented when the animals were given CGP39551 (the carboxyethylester of CGP 37849; DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid), a competitive N-methyl-Daspartate (NMDA) receptor antagonist, before experiencing stress. In contrast, the anxiolytic drug diazepam did not block the stress effects on hippocampal plasticity. Thus, the effects of stress on subsequent LTP and LTD appear to be mediated through the activation of the NMDA subtype of glutamate receptors. Such modifications in hippocampal plasticity may contribute to learning and memory impairments associated with stress.It is now well-documented that behavioral stress impairs an organism's subsequent ability to acquire and retain information, a phenomenon known as "learned helplessness" (1, 2). When events are perceived to be uncontrollable, the organism learns that its behavior and outcomes are independent; this learning seems to produce cognitive, emotional, and motivational deficits (for review, see ref.3). For instance, Vietnam combat veterans diagnosed with posttraumatic stress disorder exhibit marked deficits in immediate, delayed, and long-term recall tasks when compared with other military enlistees not diagnosed with posttraumatic stress disorder (4, 5). In laboratory settings, dogs, cats, rats, and even fish have shown learned helplessness after exposure to a series of inescapable electric shocks (3). It now appears that stress interferes with performance in hippocampal-dependent tasks such as Olton's radial-arm maze (6, 7), but facilitates performance in hippocampal-independent tasks such as delay eyeblink conditioning in both rats (8) and humans (9).Rats exposed to uncontrollable stress (restraint plus shock) also show an impairment in long-term potentiation (LTP) in the hippocampus (10). Interestingly, rats able to control shock schedule do not show LTP impairment unlike "yoked" animals receiving the identical shock schedule without control (11). LTP refers to a sustained enhancement of synaptic transmission that follows a brief tetanic stimulation of afferent fibers (12, 13). In addition to longevity, LTP is rapidly induced, strengthened by repetition, demonstrates specificity and associativity, and occurs prominently in the hippocampus, a structure implicated in learning and memory processes (14). Because of these properties, LTP is widely regarded as a potential synaptic mechanism underlying information ...