Cellular mechanisms of synaptic plasticity: perspectives of studying the role of calcium.
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Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity.
The functional significance of cyclooxygenases (COX-1 and -2), the key enzymes that convert arachidonic acid (AA) to prostaglandins (PGs) in brain, is unclear, although they have been implicated in cellular functions and in some neurologic disorders, including stroke, epilepsy, and Alzheimer's disease. Recent evidence that COX-2 is expressed in postsynaptic dendritic spines (which are specialized structures involved in synaptic signaling) and is regulated by synaptic activity implies participation of COX-2 in neuronal plasticity. However, direct evidence is lacking. Here we demonstrate that selective COX-2 inhibitors significantly reduced postsynaptic membrane excitability, back-propagating dendritic action potential-associated Ca2+ influx, and long-term potentiation (LTP) induction in hippocampal dentate granule neurons, while a COX-1 inhibitor is ineffective. All of these actions were effectively reversed by exogenous application of PGE2 but not of PGD2 or PGF(2alpha). Our results indicate that COX-2-generated PGE2 regulates membrane excitability and long-term synaptic plasticity in hippocampal perforant path-dentate gyrus synapses.
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Deletion of the nuclear receptor Nr2e1 impairs synaptic plasticity and dendritic structure in the mouse dentate gyrus.
The spontaneous or targeted deletion of the nuclear receptor transcription factor Nr2e1 produces a mouse that shows hypoplasia of the hippocampal formation and reduced neurogenesis in adult mice. In these studies we show that hippocampal synaptic transmission appears normal in the dentate gyrus and cornu ammonis 1 subfields of adult mice that lack Nr2e1 (Nr2e1-/-), and that fEPSP shape, paired-pulse responses, and short-term plasticity are not substantially altered in either subfield. In contrast, the expression of long-term potentiation is selectively impaired in the dentate gyrus, and not in the cornu ammonis 1 subfield. Golgi analysis revealed that there was a significant reduction in both dendritic branching and dendritic length that was specific to dentate gyrus granule cells in the Nr2e1-/- mice. These results indicate that Nr2e1 deletion can significantly alter both synaptic plasticity and dendritic structure in the dentate gyrus.
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[Effect of selective protein kinase C inhibitor on synaptic plasticity of command neurons of defensive behaviour during sensitization in snails].
Polymyxin B (proteinkinase C inhibitor) effects on nociceptive sensitization of semiintact preparation were investigated in LP11 and RP11 snail neurons. It was found that application of sensitizing stimuli to control snail head initiated neural membrane depolarization, increase its excitability as well as depression of neural responses evoked by sensory stimulation during short-term stage. Polymyxin B application suppressed neural responses evoked by sensitizing (nociceptive) stimuli. At the same time changes in neural membrane excitability as well as neural responses evoked by tactile stimulation of snail foot or chemical stimulation of snail head were similar with ones in control snails. Polymyxin Bdid does not change the depression of neural responses evoked by tactile stimulation of snail head during short-term stages of sensitization but significantly suppressed facilitation of neural responses evoked by tactile stimulation of snail head during long-term stage of sensitization. It was suggested that proteinkinase C is involved in regulation of nociceptive mechanisms as well as in plasticity selective induction mechanisms in command neuron synaptic inputs activated by tactile stimulation of snail head.
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Intrinsic and synaptic plasticity in the vestibular system.
The vestibular system provides an attractive model for understanding how changes in cellular and synaptic activity influence learning and memory in a quantifiable behavior, the vestibulo-ocular reflex. The vestibulo-ocular reflex produces eye movements that compensate for head motion; simple yet powerful forms of motor learning calibrate the circuit throughout life. Learning in the vestibulo-ocular reflex depends initially on the activity of Purkinje cells in the cerebellar flocculus, but consolidated memories appear to be stored downstream of Purkinje cells, probably in the vestibular nuclei. Recent studies have demonstrated that the neurons of the vestibular nucleus possess the capacity for both synaptic and intrinsic plasticity. Mechanistic analyses of a novel form of firing rate potentiation in neurons of the vestibular nucleus have revealed new rules of plasticity that could apply to spontaneously firing neurons in other parts of the brain.
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Functional synaptic plasticity in hypothalamic magnocellular neurons.
The hypothalamic-neurohypophysial system undergoes dramatic morphological plasticity in response to physiological activation during parturition/lactation and dehydration, including somatic swelling, decreased glial coverage and increased synaptic innervation of the magnocellular neuroendocrine cells. Recent in-vitro electrophysiological studies in hypothalamic slices have demonstrated that coordinate changes in the synaptic physiology of the magnocellular neurons also occur under these conditions. Thus, the synaptic release of glutamate and GABA onto magnocellular neurons is increased during lactation and with chronic dehydration, and changes in postsynaptic glutamate and GABAA receptor expression lead to alterations of the functional properties of the glutamate and GABAA receptor channels. The presynaptic noradrenergic facilitation of glutamate release and inhibition of GABA release is also markedly enhanced following chronic dehydration. Additionally, both parturition and chronic dehydration are accompanied by an increase in the tonic activation of presynaptic metabotropic glutamate receptors due to the higher ambient glutamate concentration caused by decreased glial coverage and the resultant reduction in glutamate reuptake. Together, these electrophysiological studies reveal profound functional plasticity in the synaptic physiology of magnocellular neurons at parturition and following dehydration. The plastic changes support an increase in the excitability of magnocellular neuroendocrine cells by increasing glutamate inputs, decreasing GABA inputs, enhancing excitatory noradrenergic modulation, and reducing synaptic glutamatergic noise.
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The contribution of activity-dependent synaptic plasticity to classical conditioning in Aplysia.
Plasticity at central synapses has long been thought to be the most likely mechanism for learning and memory, but testing that idea experimentally has proven to be difficult. For this reason, we have developed a simplified preparation of the Aplysia siphon withdrawal reflex that allows one to examine behavioral learning and memory while simultaneously monitoring synaptic connections between individual identified neurons in the CNS. We previously found that monosynaptic connections from LE siphon sensory neurons to LFS siphon motor neurons make a substantial contribution to the reflex in the siphon withdrawal preparation (Antonov et al., 1999a). We have now used that preparation to assess the contribution of various cellular mechanisms to classical conditioning of the reflex with a siphon tap conditioned stimulus (CS) and tail shock unconditioned stimulus (US). We find that, compared with unpaired training, paired training with the CS and US produces greater enhancement of siphon withdrawal and evoked firing of LFS neurons, greater facilitation of the complex PSP elicited in an LFS neuron by the siphon tap, and greater facilitation of the monosynaptic PSP elicited by stimulation of a single LE neuron. Moreover, the enhanced facilitation of monosynaptic LE-LFS PSPs is greater for LE neurons that fire during the siphon tap and correlates significantly with the enhancement of siphon withdrawal and evoked firing of the LFS neurons. These results provide the most direct evidence to date that activity-dependent plasticity at specific central synapses contributes to behavioral conditioning and support the idea that synaptic plasticity is a mechanism of learning and memory more generally.
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AMPA receptor trafficking: a road map for synaptic plasticity.
Most excitatory transmission in the brain is mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPA receptors). Therefore, the presence of these receptors at synapses has to be carefully regulated in order to ensure correct neuronal communication. Interestingly, AMPA receptors are not static components of synapses. On the contrary, they are continuously being delivered and removed in and out of synapses in response to neuronal activity. This dynamic behavior of AMPA receptors is an important mechanism to modify synaptic strength during brain development and also during experience-dependent plasticity. AMPA receptor trafficking involves an intricate network of protein-protein interactions that start with the biosynthesis of the receptors, continues with their transport along dendrites, and ends with their local insertion and removal from synapses. The molecular and cellular mechanisms that regulate each of these processes, and their importance for synaptic plasticity, are now starting to be unraveled.
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BCL-xL regulates synaptic plasticity.
Mitochondria are the predominant organelle within many presynaptic terminals. During times of high synaptic activity, they affect intracellular calcium homeostasis and provide the energy needed for synaptic vesicle recycling and for the continued operation of membrane ion pumps. Recent discoveries have altered our ideas about the role of mitochondria in the synapse. Mitochondrial localization, morphology, and docking at synaptic sites may indeed alter the kinetics of transmitter release and calcium homeostasis in the presynaptic terminal. In addition, the mitochondrial ion channel BCL-xL, known as a protector against programmed cell death, regulates mitochondrial membrane conductance and bioenergetics in the synapse and can thereby alter synaptic transmitter release and the recycling of pools of synaptic vesicles. BCL-xL, therefore, not only affects the life and death of the cell soma, but its actions in the synapse may underlie the regulation of basic synaptic processes that subtend learning, memory and synaptic development.
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The role of protein phosphatase-1 in the modulation of synaptic and structural plasticity.
Synaptic plasticity is a phenomenon contributing to changes in the efficacy of neuronal transmission. These changes are widely believed to be a major cellular basis for learning and memory. Protein phosphorylation is a key biochemical process involved in synaptic plasticity that operates through a tight balance between the action of protein kinases and protein phosphatases (PPs). Although the majority of research in this field has concentrated primarily on protein kinases, the significant role of PPs is becoming increasingly apparent. This review examines one such phosphatase, PP1, and highlights recent advances in the understanding of its intervention in synaptic and structural plasticity and the mechanisms of learning and memory.
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Spike-timing-dependent synaptic plasticity depends on dendritic location.
In the neocortex, each neuron receives thousands of synaptic inputs distributed across an extensive dendritic tree. Although postsynaptic processing of each input is known to depend on its dendritic location, it is unclear whether activity-dependent synaptic modification is also location-dependent. Here we report that both the magnitude and the temporal specificity of spike-timing-dependent synaptic modification vary along the apical dendrite of rat cortical layer 2/3 pyramidal neurons. At the distal dendrite, the magnitude of long-term potentiation is smaller, and the window of pre-/postsynaptic spike interval for long-term depression (LTD) is broader. The spike-timing window for LTD correlates with the window of action potential-induced suppression of NMDA (N-methyl-D-aspartate) receptors; this correlation applies to both their dendritic location-dependence and pharmacological properties. Presynaptic stimulation with partial blockade of NMDA receptors induced LTD and occluded further induction of spike-timing-dependent LTD, suggesting that NMDA receptor suppression underlies LTD induction. Computer simulation studies showed that the dendritic inhomogeneity of spike-timing-dependent synaptic modification leads to differential input selection at distal and proximal dendrites according to the temporal characteristics of presynaptic spike trains. Such location-dependent tuning of inputs, together with the dendritic heterogeneity of postsynaptic processing, could enhance the computational capacity of cortical pyramidal neurons.
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Current advances in local protein synthesis and synaptic plasticity.
Local or dendritic protein synthesis is required for long-term functional synaptic change, such as long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD both rely on similar signal transduction cascades, which regulate translation initiation. Current research indicates that the specificity by which new proteins participate in either LTP or LTD may be determined in part by specific RNA-binding proteins as well as activity-dependent capture.
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Synaptic plasticity in rat hippocampal slice cultures: local "Hebbian" conjunction of pre- and postsynaptic stimulation leads to distributed synaptic enhancement.
A central theme in neurobiology is the search for the mechanisms underlying learning and memory. Since the seminal work, first of Cajal and later of Hebb, the synapse is thought to be the basic "storing unit." Hebb proposed that information is stored by correlation: synapses between neurons, which are often coactive, are enhanced. Several recent findings suggest that such a mechanism is indeed operative in the central nervous system. Pairing of activity on presynaptic fibers with strong postsynaptic depolarization results in synaptic enhancement. While there is substantial evidence in favor of a postsynaptic locus for detection of the synchronous pre- and postsynaptic event and subsequent initiation of synaptic enhancement, the locus of this enhancement and its ensuing persistence is still disputed: both pre- and postsynaptic contributions have been suggested. In all previous studies, the enhancement was presumed to be specific to the synapses where synchronous pre- and postsynaptic stimulation was applied. We report here that two recording techniques--optical recording, using voltage-sensitive dyes, and double intracellular recordings--reveal that synaptic enhancement is not restricted to the stimulated cell. Although we paired single afferent volleys with intracellular stimulation confined to one postsynaptic cell, we found that strengthening also occurred on synapses between the stimulated presynaptic fibers and neighboring cells. This suggests that synaptic enhancement by the "paired-stimulation paradigm" is not local on the presynaptic axons and that, in fact, the synapses of many neighboring postsynaptic cells are enhanced.
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Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation.
Local protein translation in dendrites could be a means for delivering synaptic proteins to their sites of action, perhaps in a spatially regulated fashion that could contribute to plasticity. To directly test the functional role of dendritic translation of calcium/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha) in vivo, we mutated the endogenous gene to disrupt the dendritic localization signal in the mRNA. In this mutant mouse, the protein-coding region of CaMKIIalpha is intact, but mRNA is restricted to the soma. Removal of dendritic mRNA produced a dramatic reduction of CaMKIIalpha in postsynaptic densities (PSDs), a reduction in late-phase long-term potentiation (LTP), and impairments in spatial memory, associative fear conditioning, and object recognition memory. These results demonstrate that local translation is important for synaptic delivery of the kinase and that local translation contributes to synaptic and behavioral plasticity.
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Lipid signaling and synaptic plasticity.
Lipids are essential components of plasma- and organelle-membranes, not only providing a frame for embedded proteins (e.g., receptors and ion channels) but also functioning as reservoirs for lipid mediators. Increasing evidence indicates that bioactive lipids such as eicosanoids, endocannabinoids, and lysophospholipids serve as intercellular and intracellular signaling molecules participating in physiological and pathological functions in the brain. The discovery of some of these lipid receptors and novel lipid signaling mediators has sparked an intense interest in lipidomic neurobiology research. Classic prostaglandins (PGD(2), PGE(2), PGF(2alpha), PGI(2), and TXA(2)), catalyzed by cyclooxygenases (COX), are synthesized from arachidonic acid (AA). Experimental studies demonstrate that prostaglandin E(2) (PGE(2)), mainly derived from the COX-2 reaction, is an important mediator, acting as a retrograde messenger via a presynaptic PGE(2) subtype 2 receptor (EP(2)) in modulation of synaptic events. Novel prostaglandins (prostaglandin glycerol esters and prostaglandin ethanolamides) are COX-2 oxidative metabolites of endogenous cannabinoids (2-arachidonyl glycerol and arachidonyl ethanolamide). Recent evidence suggests that these new types of prostaglandins are likely novel signaling mediators involved in synaptic transmission and plasticity. This means that COX- 2 plays a central role in metabolisms of AA and endocannabinoids (eCBs) and productions of AA- and eCB- derived prostaglandins. Thus, in the present review article, the authors will mainly discuss COX-2 regulation of prostaglandin signaling in modulation of hippocampal synaptic transmission and plasticity.
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Analysis of neural cell functions in gene knockout mice: electrophysiological investigation of synaptic plasticity in acute hippocampal slices.
Several knockout mice deficient in transferases, required for glycosylation of cell adhesion and extracellular matrix molecules, have recently been produced. Extracellular recordings of field excitatory postsynaptic potentials in acute hippocampal slices prepared from these mutant mice proved to be a highly sensitive method to reveal the roles of transferases and related carbohydrates in synaptic transmission and plasticity. Although most available data have been collected for synaptic connections between CA3 and CA1 pyramidal cells, several other synapses are assessable for extracellular recording in the hippocampus, including connections between mossy fibers and CA3 pyramidal cells. Analysis of distinct forms of short- and long-term plasticity in these connections may be instrumental for dissection of mechanisms by which carbohydrates affect synaptic functions.
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Interaction between intracellular tetanization and pairing-induced long-term synaptic plasticity in the rat visual cortex.
Long-term changes in synaptic transmission in slices of rat visual cortex were induced either by pairing the excitatory postsynaptic potentials with postsynaptic depolarization or by intracellular tetanization without synaptic stimulation. Changes in the excitatory postsynaptic potential amplitude induced by any of the protocols applied in isolation persisted for longer than 1 h. Pairing-induced long-term potentiation was input specific. We studied the interaction between intracellular tetanization and pairing-induced plasticity by applying the two protocols one after the other at 10-min intervals. The pairing procedure applied after intracellular tetanization did not lead to any further potentiation, but to a depotentiation of the potentiated inputs. A second pairing protocol applied 10 min later led to further depotentiation, while previously unaffected inputs became weakly depressed. If intracellular tetanization was applied after the pairing procedure, the synaptic responses did not change immediately, but a slow return of the excitatory postsynaptic potential amplitude to the control level could be observed. Therefore, intracellular tetanization is not capable of inducing further potentiation after pairing, and pairing cannot further potentiate the inputs which have already been potentiated by intracellular tetanization. The maintenance of long-term potentiation induced by any of the protocols was impaired by successive application of another procedure. These results suggest a similarity of the mechanisms of synaptic changes induced by the two protocols and demonstrate that the direction of synaptic gain change depends on the history of the synapse.
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Intracellular studies on cortical synaptic plasticity. Conditioning effect of antidromic activation on test-EPSPs.
1. An intracellular study on pyramidal tract (PT) neurons in the cat's motor cortex was carried out to examine whether their antidromic activation would be able to induce plastic changes in the efficacy of the synapses situated on their membrane. 2. The experimental paradigm was based on the principles of classical conditioning. It included habituation, pseudoconditioning, conditioning and extinction procedures. The antidromic spike was regarded as an unconditioned stimulus while excitatory postsynaptic potentials (EPSPs) evoked by thalamic (n. ventralis lateralis), callosal and somatosensory afferents served as conditioned stimuli. Stimulus pairs were given, consisting of EPSPs and antidromic spikes with various time intervals, and the stimulus sequences were at a 0.2--1.0/s frequency. 3. Reversible, short-term (3--28 min) enhancement of synaptic excitability was observed in 27% of the PT cells after conditioning with 60--150 stimulus pairs. 4. EPSP-spike and spike-EPSP sequences were equally effective, but plastic changes were induced only by stimulus pairs with less than 100 ms interstimulus intervals. 5. Facilitated EPSP states were frequently accompanied by changes in membrane potential, membrane resistance and firing activity. 6. In repeated conditioning series, the temporal parameters of conditioning changes, the number of stimuli necessary for full development of facilitation, and some membrane parameters showed marked alterations. 7. Conditioned plastic changes in synaptic efficacy showed analogies with associative learning: (a) they were specific to the pairing procedure, because randomized presentation of EPSPs and antidromic spikes never produced synaptic facilitation; (b) unpaired spike trains used as unconditioned stimuli (of 10--200/s frequency and 1--20 s duration) caused only a minor degree of facilitation as compared with EPSP-spike pairings; (c) changes in synaptic efficacy were subject to extinction. 8. The present findings indicate that the plastic changes in synaptic transmission may be localized to the postsynaptic membrane of the conditioned PT cells.
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