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PubMed2006

Synaptic plasticity in vitro and in silico: insights into an intracellular signaling maze.

Synaptic plasticity provides a record of neuronal activity and is a likely basis for memory. The early apparent simplicity of the process of synaptic plasticity has been lost in a flood of experimental data that now implicates some 200 signaling molecules in cellular memory. It is now clear that these signaling networks perform surprisingly sophisticated cellular decisions that weigh factors such as input patterns, location of stimulus, history of activity, and context. Computer models have followed experiments into this maze of molecular detail, often matching closely with their experimental counterparts, but perhaps losing simplicity in the process. Here, we suggest that the merger of models and experiment have begun to restore the earlier simplicity by outlining a few key functional roles for signaling networks in synaptic plasticity. In this review, we discuss the current state of understanding of synaptic plasticity in terms of models and experiments.

Animals↗
PubMed2005

Lipid signaling: sleep, synaptic plasticity, and neuroprotection.

Increasing evidence indicates that bioactive lipids participate in the regulation of synaptic function and dysfunction. We have demonstrated that signaling mediated by platelet-activating factor (PAF) and cyclooxygenase (COX)-2-synthesized PGE2 is involved in synaptic plasticity, memory, and neuronal protection [Clark GD, Happel LT, Zorumski CF, Bazan NG. Enhancement of hippocampal excitatory synaptic transmission by platelet-activating factor. Neuron 1992; 9:1211; Kato K, Clark GD, Bazan NG, Zorumski CF. Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation. Nature 1994; 367:175; Izquierdo I, Fin C, Schmitz PK, et al. Memory enhancement by intrahippocampal, intraamygdala or intraentorhinal infusion of platelet-activating factor measured in an inhibitory avoidance. Proc Natl Acad Sci USA 1995; 92:5047; Chen C, Magee CJ, Bazan NG. Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity. J Neurophysiol 2002; 87:2851]. Recently, we found that prolonged continuous wakefulness (primarily rapid eye movement (REM)-sleep deprivation, SD) causes impairments in hippocampal long-term synaptic plasticity and hippocampus-dependent memory formation [McDermott CM, LaHoste GJ, Chen C, Musto A, Bazan NG, Magee JC. Sleep deprivation causes behavioral, synaptic, and membrane excitability alterations in hippocampal neurons. J Neurosci 2003; 23:9687]. To explore the mechanisms underlying SD-induced impairments, we have studied several bioactive lipids in the hippocampus following SD. It appears that SD causes increases in prostaglandin D2 (PGD2) and 2-arachidonylglycerol (2-AG), and a decrease in PGE2, suggesting that these lipid messengers participate in memory consolidation during REM sleep. We have also explored the formation of endogenous neuroprotective lipids. Toward this aim, we have used ischemia-reperfusion damage and LC-PDA-ESI-MS-MS-based lipidomic analysis and identified docosanoids derived from synaptic phospholipid-enriched docosahexaenoic acid. Some of the docosanoids exert potent neuroprotective bioactivity [Marcheselli VL, Hong S, Lukiw WJ, et al. Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 2003; 278:43807; Mukherjee PK, Marcheselli VL, Serhan CN, Bazan, NG. Neuroprotectin D1: A docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Nat Acad Sci USA 2004; 101:8491). Taken together, these observations that signaling lipids participate in synaptic plasticity, cognition, and survival indicate that lipid signaling is closely associated with several functions (e.g; learning and memory, sleep, and experimental stroke) and pathologic events. Alterations in endogenous signaling lipids or their receptors resulting from drug abuse lead to changes in synaptic circuitry and induce profound effects on these important functions. In the present article, we will briefly review bioactive lipids involved in sleep, synaptic transmission and plasticity, and neuroprotection, focusing mainly on our experimental studies and how these signaling molecules are related to functions and implicated in some neurologic disorders.

Animals↗
PubMed2000

Synaptic plasticity in the human dentate gyrus.

Activity-dependent plasticity is a fundamental feature of most CNS synapses and is thought to be a synaptic correlate of memory in rodents. In humans, NMDA receptors have been linked to verbal memory processes, but it is unclear whether NMDA receptor-dependent synaptic plasticity can be recruited for information storage in the human CNS. Here we have for the first time analyzed different forms of synaptic plasticity in human hippocampus. In human subjects who show a morphologically intact hippocampus that is not the primary seizure focus, NMDA receptor-dependent long-term potentiation (LTP) and forskolin-induced long-lasting potentiation are readily induced at the perforant path-dentate gyrus synapse. In this group, long-term potentiation could be partially depotentiated by low-frequency stimulation. Because patients with a hippocampal seizure focus showed a marked reduction in verbal memory performance in previous studies, we asked whether synaptic plasticity is similarly affected by the presence of a hippocampal primary seizure focus. We found that the amount of potentiation induced by high-frequency stimulation or perfusion of forskolin is dramatically reduced in this patient group. In addition, low-frequency stimulation is not effective in inducing synaptic depression. In summary, we show that activity-dependent synaptic plasticity with properties similar to the rodent is available for information storage in the human hippocampus. Because both verbal memory processes and synaptic plasticity are impaired by a hippocampal seizure focus, we suggest that impaired synaptic plasticity may contribute to deficient declarative memory in human temporal lobe epilepsy.

1-Methyl-3-isobutylxanthine↗
PubMed2006

Endocannabinoid-mediated synaptic plasticity in the CNS.

Changes in synaptic efficacy are thought to be crucial to experience-dependent modifications of neural function. The diversity of mechanisms underlying these changes is far greater than previously expected. In the last five years, a new class of use-dependent synaptic plasticity that requires retrograde signaling by endocannabinoids (eCB) and presynaptic CB1 receptor activation has been identified in several brain structures. eCB-mediated plasticity encompasses many forms of transient and long-lasting synaptic depression and is found at both excitatory and inhibitory synapses. In addition, eCBs can modify the inducibility of non-eCB-mediated forms of plasticity. Thus, the eCB system is emerging as a major player in synaptic plasticity. Given the wide distribution of CB1 receptors in the CNS, the list of brain structures and synapses expressing eCB-mediated plasticity is likely to expand.

Animals↗
PubMed1999

Adenosine modulates synaptic plasticity in hippocampal slices from aged rats.

Adenosine is known to modulate synaptic plasticity in the hippocampus of young animals through activation of adenosine A1 receptors. The objective of the present study is to investigate whether the modulatory role of adenosine on phenomena of synaptic plasticity is maintained or modified in the hippocampus of aged animals. We compared the effects of the selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 50 nM), on paired-pulse facilitation (PPF), long-term depression (LTD), long-term potentiation (LTP) and depotentiation elicited in hippocampal slices taken from young adult (5-6 weeks) and old (2 years old) male Wistar rats. DPCPX attenuated PPF both in young (1.64 +/- 0.05 vs. 1.76 +/- 0.05%, n = 6) and in old rats (1.33 +/- 0.05 vs. 1.55 +/- 0.1%, n = 6). LTD was only observed in the presence of DPCPX in both young (21.3 +/- 0.6%, n = 4) and old rats (14.4 +/- 0.9%, n = 6). LTP induced by high-frequency stimulation (HFS) was not significantly different in young and old animals, in the presence or in the absence of DPCPX. A larger depotentiation was observed in the presence of DPCPX in young rats (27.6 +/- 4.4% vs. 16.8 +/- 4.7%, n = 7) as well as in old rats (41.3 +/- 5.1% vs. 16.1 +/- 2.7%, n = 6). LTP induced by theta-burst stimulation was observed only in the presence of DPCPX (53.9 +/- 4.9%, n = 5) in young rats, but could be obtained either in the control solution (81.8 +/- 17.9%, n = 7) or in the presence of DPCPX (98.5 +/- 24.2%, n = 7) in old rats. The modulatory role of endogenous adenosine on synaptic plasticity is generally maintained in aged animals. Drugs interfering with adenosine A1 receptor effects could then be used in old animals to modify synaptic plasticity with relevant behavioural consequences.

Adenosine↗
PubMed2005

Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2.

Studies on various forms of synaptic plasticity have shown a link between messenger RNA translation, learning and memory. Like memory, synaptic plasticity includes an early phase that depends on modification of pre-existing proteins, and a late phase that requires transcription and synthesis of new proteins. Activation of postsynaptic targets seems to trigger the transcription of plasticity-related genes. The new mRNAs are either translated in the soma or transported to synapses before translation. GCN2, a key protein kinase, regulates the initiation of translation. Here we report a unique feature of hippocampal slices from GCN2(-/-) mice: in CA1, a single 100-Hz train induces a strong and sustained long-term potentiation (late LTP or L-LTP), which is dependent on transcription and translation. In contrast, stimulation that elicits L-LTP in wild-type slices, such as four 100-Hz trains or forskolin, fails to evoke L-LTP in GCN2(-/-) slices. This aberrant synaptic plasticity is mirrored in the behaviour of GCN2(-/-) mice in the Morris water maze: after weak training, their spatial memory is enhanced, but it is impaired after more intense training. Activated GCN2 stimulates mRNA translation of ATF4, an antagonist of cyclic-AMP-response-element-binding protein (CREB). Thus, in the hippocampus of GCN2(-/-) mice, the expression of ATF4 is reduced and CREB activity is increased. Our study provides genetic, physiological, behavioural and molecular evidence that GCN2 regulates synaptic plasticity, as well as learning and memory, through modulation of the ATF4/CREB pathway.

Animals↗
PubMed2001

Activity- and age-dependent GABAergic synaptic plasticity in the developing rat hippocampus.

Activity-dependent plasticity of GABAergic synaptic transmission was investigated in rat hippocampal slices obtained between postnatal day (P) 0-15 using the whole-cell patch-clamp recording technique. Spontaneous GABA(A) receptor-mediated postsynaptic currents (sGABA(A)-PSCs) were isolated in the presence of ionotropic glutamate receptor antagonists. A conditioning protocol relevant to the physiological condition, consisting of repetitive depolarizing pulses (DPs) at 0.1 Hz, was able to induce long-lasting changes in both frequency and amplitude of sGABA(A)-PSCs between P0 and P8. Starting from P12, DPs were unable to induce any form of synaptic plasticity. The effects of DPs were tightly keyed to the frequency at which they were delivered. When delivered at a lower (0.05 Hz) or higher (1 Hz) frequency, DPs failed to induce any long-lasting change in the frequency or amplitude of sGABA(A)-PSCs. In two cases, DPs were able to activate sGABA(A)-PSCs in previously synaptically silent cells at P0-1. These results show that long-term changes in GABAergic synaptic activity can be induced during a restricted period of development by a conditioning protocol relevant to the physiological condition. It is suggested that such activity-induced modifications may represent a physiological mechanism for the functional maturation of GABAergic synaptic transmission.

Action Potentials↗
PubMedDate not supplied

[Synaptic plasticity in the hippocampus during afferent activation reproducing a theta-rhythm pattern (theta plasticity)].

The data are reviewed concerning synaptic plasticity of the hippocampal monosynaptic pathways evoked by afferent activation which simulates activity of neurons in theta-rhythm. Activation with short high-frequency bursts applied with 5 Hz frequency effectively induces long-term potentiation. In contrast, activation with single pulses at 5 Hz causes the depotentiation or even long-term depression of the activated synapses. "In-phase" activation of two afferent pathways in the theta-rhythm induces long-term potentiation, while the "out-of-phase" activation induces long-term depression of a "weak"" pathway. A train of 30-50 pulses at 5 Hz evokes heterosynaptic short-term depression, i.e., a suppression of all synaptic inputs for 1 min. So-called "hidden" plasticity (the enhancement of the effect of delayed activation in producing long-term depression) is also effectively evoked by the theta-like activatory patterns. Therefore, practically all known types of synaptic plasticity can be effectively evoked by the afferent activation which reproduce the pattern of the hippocampal theta-rhythm. These phenomena can underlie the theta-rhythm participation in learning and memory.

Afferent Pathways↗
PubMed2000

The role of mammalian ionotropic receptors in synaptic plasticity: LTP, LTD and epilepsy.

Synaptic plasticity is the foremost candidate mechanism to explain the rapid acquisition of memories. In the mammalian brain, the NMDA subclass of glutamate receptors plays a central role in the induction of several forms of use-dependent plasticity. The finding that modifications in synaptic strength are largely expressed by receptors of the AMPA subclass has focused attention on molecular mechanisms that affect their function and targeting. Receptor plasticity has also been reported in pathological situations, notably in animal and human forms of epilepsy. Which of these changes are causally implicated in the generation of seizures, and which may be compensatory or neuroprotective adaptations, has not been fully resolved.

Animals↗
PubMed1991

Astrocytes within the hypothalamic arcuate nucleus contain estrogen-sensitive peroxidase, bind fluorescein-conjugated estradiol, and may mediate synaptic plasticity in the rat.

Estrogen treatment induces synaptic plasticity accompanied by damaged structures and aggregates of peroxidase in astrocytes in the hypothalamic arcuate nucleus of the rat. Synaptic plasticity also occurs within the arcuate nucleus after physiologic surges of estrogen. Although the function of estrogen-induced peroxidase is unclear at present, in other systems peroxidase can generate free radicals by catalyzing the oxidation of some molecules, including estrogen. Because free radicals underlie remodeling in a number of tissues, estrogen-induced free radicals could mediate synaptic remodeling within the arcuate nucleus. Although they contain estrogen-inducible peroxidase, astrocytes do not contain estrogen receptors as measured by conventional techniques, suggesting that estrogen-inducible peroxidase arises from some novel mechanism. Estrogen could induce peroxidase within receptor-deficient astrocytes by binding to receptors in neurons and stimulating the release of some factor that interacts with astrocytes. Alternatively, estrogen could act directly on astrocytes in the absence of estrogen receptors. Although astrocytes in the hypothalamus of the rat do not contain classical nuclear estrogen receptors, they do bind fluorescein-conjugated estradiol in extranuclear sites. The distribution of fluorescein-conjugated estradiol binding within the hypothalamus overlaps that of peroxidase-rich astrocytes, and double labeling reveals many cells with the stellate morphology of astrocytes, containing both peroxidase and fluorescein-conjugated estradiol binding. However, because peroxidase and fluorescein-conjugated estradiol always occupy different compartments of the cell, the fluorescein-conjugated estradiol is not binding to peroxidase.

Animals↗
PubMedDate not supplied

[The problem of adequacy of the methods applying for testing of synaptic plasticity during processes of learning].

Analysis of only the postsynaptic responses seems to be insufficient for studying the synaptic plasticity in learning, because they reflect not only synaptic modifications. The adequacy of brain slices application for investigation of the synaptic plasticity in learning per se has not been strictly specified. Learning processed can be adequately studied only in awake animals. However, traditional methods of field potential recording in response to stimulation of certain inputs that are well interpretable in vitro studies seem to be inadequate for in vivo testing synaptic plasticity. Single unit activity recording in pre- and postsynaptic fields during learning and direct threshold stimulation of monosynaptic inputs to a postsynaptic cell are suggested as a promising strategy for investigation of synaptic plasticity. Since the recording area is not deafferrented in a freely moving animal (as distinct from brain slices), the spontaneous activity in the neural network can interfere with responses to a testing stimulus. Computer simulation demonstrates that the interaction between spontaneous afferentation and testing stimulation can produce an illusion of synaptic modifications. Computer simulation of a neurophysiological experiment is proposed as a preliminary method for the reduction of the effect of spontaneous afferentation on the probability of the postsynaptic response.

Animals↗
PubMed2001

Conditions that affect sleep alter the expression of molecules associated with synaptic plasticity.

Many theories propose that sleep serves a purpose in synaptic plasticity. We tested the hypothesis, therefore, that manipulation of sleep would affect the expression of molecules known to be involved in synaptic plasticity. mRNA expression of four molecules [brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeleton-associated protein (Arc), matrix metalloproteinase-9 (MMP-9), and tissue plasminogen activator (tPA)] was determined after 8 h of sleep deprivation and after 6 h of a mild increase in ambient temperature, a condition that enhances sleep in rats. After sleep deprivation, BDNF, Arc, and tPA mRNAs in the cerebral cortex increased while MMP-9 mRNA levels decreased. Conversely, after enhanced ambient temperature, BDNF, Arc, and tPA mRNAs decreased while MMP-9 mRNA increased. In the hippocampus, sleep deprivation did not significantly affect BDNF and tPA expression, although Arc mRNA increased and MMP-9 mRNA decreased. Brain temperature enhancement decreased Arc mRNA levels in the hippocampus but did not affect BDNF, MMP-9, or tPA in this area. Results are consistent with the notion that sleep plays a role in synaptic plasticity.

Animals↗
PubMed2003

Synaptic plasticity and cell cycle activation in neurons are alternative effector pathways: the 'Dr. Jekyll and Mr. Hyde concept' of Alzheimer's disease or the yin and yang of neuroplasticity.

Mental actions are based on the dynamic organization of neuronal networks. In particular, phylogenetically young brain areas (e.g., cortical associative circuits) involved in the realization of higher brain functions are continuously re-adjusted to meet environmental demands. The mechanisms of synaptic plasticity, i.e., of structural stabilization and labilization underlying a life-long synaptic remodelling, are largely based on external morphoregulatory cues and internal signalling pathways that non-neuronal cells have phylogenetically acquired to sense their relationship to the local neighbourhood and to control after development is completed proliferation and differentiation in the process of tissue repair and regeneration. After having withdrawn from the cell cycle, differentiated neurons are, thus, able to use molecular mechanisms primarily developed to control proliferation alternatively to control synaptic plasticity. The existence of these alternative effector pathways within a neuron puts it at risk to erroneously convert signals derived from plastic synaptic changes into positional cues that will activate the cell cycle. This cell cycle activation potentially links synaptic plasticity to cell death. Preventing cell cycle activation by locking neurons in a differentiated but still highly plastic phenotype will, thus, be crucial to prevent neurodegeneration.

Alzheimer Disease↗
PubMed2003

Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity.

This study was designed to identify molecular mechanisms by which exercise affects synaptic-plasticity in the hippocampus, a brain area whose function, learning and memory, depends on this capability. We have focused on the central role that brain-derived neurotrophic factor (BDNF) may play in mediating the effects of exercise on synaptic-plasticity. In fact, this impact of exercise is exemplified by our finding that BDNF regulates the mRNA levels of two end products important for neural function, i.e. cAMP-response-element binding (CREB) protein and synapsin I. CREB and synapsin I have the ability to modify neuronal function by regulating gene-transcription and affecting synaptic transmission, respectively. Furthermore, we show that BDNF is capable of concurrently increasing the mRNA levels of both itself and its tyrosine kinaseB (TrkB) receptor, suggesting that exercise may employ a feedback loop to augment the effects of BDNF on synaptic-plasticity. The use of a novel microbead injection method in our blocking experiments and Taqman reverse transcription polymerase reaction (RT-PCR) for RNA quantification, have enabled us to evaluate the contribution of different pathways to the exercise-induced increases in the mRNA levels of BDNF, TrkB, CREB, and synapsin I. We found that although BDNF mediates exercise-induced hippocampal plasticity, additional molecules, i.e. the N-methyl-D-aspartate receptor, calcium/calmodulin protein kinase II and the mitogen-activated protein kinase cascade, modulate its effects. Since these molecules have a well-described association to BDNF action, our results illustrate a basic mechanism through which exercise may promote synaptic-plasticity in the adult brain.

Analysis of Variance↗
PubMed2004

Dual effects of ATP on rat hippocampal synaptic plasticity.

Although ATP is reported to modulate synaptic plasticity, the mechanism of action of ATP on synaptic transmission is not fully understood. Here we show that ATP enhances long-term potentiation (LTP), and P2X receptor antagonists inhibit this ATP effect, but do not affect paired pulse facilitation (PPF) in rat hippocampal slices. ATP rapidly increases intracellular calcium, and P2X receptor antagonists inhibit this increase in cultured dissociated neurons. These results indicate that ATP enhances LTP via activation of postsynaptic P2X receptors. A pertussis toxin-sensitive G-protein inhibitor significantly attenuates PPF, although it does not affect LTP, indicating that presynaptic P2Y receptors also play an important role in neuronal plasticity. We conclude that ATP modulates synaptic plasticity via dual effects on pre- and post-synaptic mechanisms.

Adenosine Triphosphate↗
PubMed1988

Quantitative morphology of synaptic plasticity in the aging brain.

Quantitation of synaptic ultrastructural changes is of great importance in neurobiology, since merely qualitative alterations, if not extreme, are not readily detectable. In the present paper we discuss our previous and present findings on the number (numerical density: Nv), size (average length of the synaptic profiles: L) and surface contact area (surface density: Sv) of the synaptic junctions in aging rodent and human brains. We found that number and size of the synapses are in a close inverse relationship so as to maintain the total surface contact are among the nerve cells constant. These three parameters are closely related to each other, their quantitation may thus represent a reliable index of the morphological aspects of synaptic plasticity, i.e. the modification of ultrastructure occurring at synaptic membranes after transient changes in synaptic activity. During aging, the morphological plasticity of synapses appears to be seriously impaired: the number of synapses and the total surface contact area among the nerve cells are markedly reduced. However, old nerve cells seem to retain the ability to modify their synaptic endings and to partially compensate for the reduced surface density of the contact zones by expanding the average size of the persisting junctions. Our recent studies on synaptic plasticity in human brains from old and demented subjects showed that while the size of the synaptic contacts remains constant, the numerical and surface densities undergo a further decrease in demented brains relative to that in normal aging.

Adult↗
PubMed2004

Biochemical mechanisms for translational regulation in synaptic plasticity.

Changes in gene expression are required for long-lasting synaptic plasticity and long-term memory in both invertebrates and vertebrates. Regulation of local protein synthesis allows synapses to control synaptic strength independently of messenger RNA synthesis in the cell body. Recent reports indicate that several biochemical signalling cascades couple neurotransmitter and neurotrophin receptors to translational regulatory factors in protein synthesis-dependent forms of synaptic plasticity and memory. In this review, we highlight these translational regulatory mechanisms and the signalling pathways that govern the expression of synaptic plasticity in response to specific types of neuronal stimulation.

Animals↗
PubMed1994

A spaceflight study of synaptic plasticity in adult rat vestibular maculas.

Behavioral signs of vestibular perturbation in altered gravity have not been well correlated with structural modifications in neurovestibular centers. This ultrastructural research investigated synaptic plasticity in hair cells of adult rat utricular maculas exposed to microgravity for nine days on a space shuttle. The hypothesis was that synaptic plasticity would be more evident in type II hair cells because they are part of a distributed modifying macular circuitry. All rats were shared with other investigators and were subjected to treatments unrelated to this experiment. Maculas were obtained from flight and control rats after shuttle return (R + 0) and nine days post-flight (R + 9). R + 9 rats had chromodacryorrhea, a sign of acute stress. Tissues were prepared for ultrastructural study by conventional methods. Ribbon synapses were counted in fifty serial sections from medial utricular macular regions of three rats of each flight and control group. Counts in fifty additional consecutive sections from one sample in each group established method reliability. All synapses were photographed and located to specific cells on mosaics of entire sections. Pooled data were analyzed statistically. Flown rats showed abnormal posture and movement at R + 0. They had statistically significant increases in total ribbon synapses and in sphere-like ribbons in both kinds of hair cells; in type II cells, pairs of synapses nearly doubled and clusters of 3 to 6 synapses increased twelve-fold. At R + 9, behavioral signs were normal. However, synapse counts remained high in both kinds of hair cells of flight maculas and were elevated in control type II cells. Only counts in type I cells showed statistically significant differences at R + 9. High synaptic counts at R + 9 may have resulted from stress due to experimental treatments. The results nevertheless demonstrate that adult maculas retain the potential for synaptic plasticity. Type II cells exhibited more synaptic plasticity, but space flight induced synaptic plasticity in type I cells.

Acoustic Maculae↗