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Results for “synaptic plasticity”

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PubMed1999

Mechanisms of synaptic vesicle recycling illuminated by fluorescent dyes.

The recycling of synaptic vesicles in nerve terminals involves multiple steps, underlies all aspects of synaptic transmission, and is a key to understanding the basis of synaptic plasticity. The development of styryl dyes as fluorescent molecules that label recycling synaptic vesicles has revolutionized the way in which synaptic vesicle recycling can be investigated, by allowing an examination of processes in neurons that have long been inaccessible. In this review, we evaluate the major aspects of synaptic vesicle recycling that have been revealed and advanced by studies with styryl dyes, focussing upon synaptic vesicle fusion, retrieval, and trafficking. The greatest impact of styryl dyes has been to allow the routine visualization of endocytosis in central nerve terminals for the first time. This has revealed the kinetics of endocytosis, its underlying sequential steps, and its regulation by Ca2+. In studies of exocytosis, styryl dyes have helped distinguish between different modes of vesicle fusion, provided direct support for the quantal nature of exocytosis and endocytosis, and revealed how the probability of exocytosis varies enormously from one nerve terminal to another. Synaptic vesicle labelling with styryl dyes has helped our understanding of vesicle trafficking by allowing better understanding of different synaptic vesicle pools within the nerve terminal, vesicle intermixing, and vesicle clustering at release sites. Finally, the dyes are now being used in innovative ways to reveal further insights into synaptic plasticity.

Animals↗

PubMed1997

Block of LTP in rat hippocampus in vivo by beta-amyloid precursor protein fragments.

The effects of beta-amyloid precursor protein (beta-APP) fragments on plasticity of glutamtatergic synaptic transmission were examined in the hippocampus of urethane anaesthetized rats. I.c.v. injection of beta-amyloid (A beta) 1-40 and 1-42 and the C-terminal fragment CT105 greatly shortened the duration of high frequency stimulation-induced long-term potentiation (LTP) of field excitatory postsynaptic potentials in the CA1 area. Whereas in vehicle injected animals LTP was stable over a 5 h recording period, doses of these peptides (A beta 1-40, 0.4 and 3.5 nmol; A beta1-42, 0.01 nmol; CT105, 0.05 nmol) which did not affect baseline synaptic transmission abolished LTP within 3-5 h. The reduced duration of this form of synaptic plasticity may contribute to the cognitive deficits in Alzheimer's disease.

Amyloid beta-Protein Precursor↗

PubMed2001

Ca2+-dependent regulation of synaptic delta2 glutamate receptor density in cultured rat Purkinje neurons.

The delta2 glutamate receptor (delta2 receptor), which is expressed abundantly at parallel fibre-Purkinje neuron synapses, has an important role in synaptogenesis and synaptic plasticity in the cerebellum. The present study examined the molecular mechanisms regulating synaptic delta2 receptor density. Immunocytochemistry, using two antibodies against the intracellular C-terminal and extracellular N-terminal regions of the delta2 receptor, indicated the reversible redistribution of postsynaptic delta2 receptors in response to either glutamatergic stimulation or enhancement of synaptic activity. The effect of glutamatergic stimulation was completely inhibited by either coapplication of the glutamate receptor antagonist or the removal of extracellular Ca2+ using EGTA and mimicked by selective activation of voltage-gated Ca2+ channels (VGCCs) with KCl, suggesting the significant role of Ca2+ influx in delta2 receptor redistribution. Biochemical examination indicated that a large amount of delta2 receptor protein was internalized following glutamatergic stimulation. These results suggest that the number of synaptic delta2 receptors is controlled by endocytosis in a synaptic activity- and intracellular Ca2+-dependent way, through which synaptogenesis and synaptic plasticity in Purkinje cells might be modulated.

Actins↗

PubMed2002

Molecular bases of long-term memories: a question of persistence.

The most distinctive attribute of long-term memory is persistence over time. New studies have uncovered many aspects of the molecular and cellular biology of synaptic plasticity, and the acquisition and consolidation of memory, which are thought to depend on synaptic plasticity. Much less, however, is known about the molecular and cellular biology of long-term memory persistence. Recent findings in the field are construed within the conceptual framework that proposes that consolidation and persistence of long-term memories require modulation of gene expression, which can culminate in synaptic remodeling. Whether modulation of gene expression, and particularly the ensuing morphological plasticity of the synapse, is permissive, causal or sufficient for the materialization and persistence of the long-term trace is, as yet, undetermined. How persistent is persistence? Renewed interest is focused on the possibility that some long-term memories consolidate anew with retrieval, and could, under certain conditions, become transiently shaky in this period of reconsolidation.

Animals↗

PubMed2002

Geometry and structural plasticity of synaptic connectivity.

Changes in synaptic connectivity patterns through the formation and elimination of dendritic spines may contribute to structural plasticity in the brain. We characterize this contribution quantitatively by estimating the number of different synaptic connectivity patterns attainable without major arbor remodeling. This number depends on the ratio of the synapses on a dendrite to the axons that pass within a spine length of that dendrite. We call this ratio the filling fraction and calculate it from geometrical analysis and anatomical data. The filling fraction is 0.26 in mouse neocortex, 0.22-0.34 in rat hippocampus. In the macaque visual cortex, the filling fraction increases by a factor of 1.6-1.8 from area V1 to areas V2, V4, and 7a. Since the filling fraction is much smaller than 1, spine remodeling can make a large contribution to structural plasticity.

Animals↗

PubMed2006

Cocaine enhances NMDA receptor-mediated currents in ventral tegmental area cells via dopamine D5 receptor-dependent redistribution of NMDA receptors.

Cocaine-induced plasticity of glutamatergic synaptic transmission in the ventral tegmental area (VTA) plays an important role in brain adaptations that promote addictive behaviors. However, the mechanisms responsible for triggering these synaptic changes are unknown. Here, we examined the effects of acute cocaine application on glutamatergic synaptic transmission in rat midbrain slices. Cocaine caused a delayed increase in NMDA receptor (NMDAR)-mediated synaptic currents in putative VTA dopamine (DA) cells. This effect was mimicked by a specific DA reuptake inhibitor and by a DA D1/D5 receptor agonist. The effect of cocaine was blocked by a DA D1/D5 receptor antagonist as well as by inhibitors of the cAMP/cAMP-dependent protein kinase A (PKA) pathway. Furthermore, biochemical analysis showed an increase in the immunoreactivity of the NMDAR subunits NR1 and NR2B and their redistribution to the synaptic membranes in VTA neurons. Accordingly, NMDAR-mediated EPSC decay time kinetics were significantly slower after cocaine, suggesting an increased number of NR2B-containing NMDARs. Finally, pharmacological analysis indicates that NR2B subunits might be incorporated in triheteromeric NR1/NR2A/NR2B complexes rather than in "pure" NR1/NR2B NMDA receptors. Together, our data suggest that acute cocaine increases NMDAR function in the VTA via activation of the cAMP/PKA pathway mediated by a DA D5-like receptor, leading to the insertion of NR2B-containing NMDARs in the membrane. These results provide a potential mechanism by which acute cocaine promotes synaptic plasticity of VTA neurons, which could ultimately lead to the development of addictive behaviors.

Animals↗

PubMed2006

Motor cortex plasticity in Parkinson's disease and levodopa-induced dyskinesias.

Experimental models of Parkinson's disease have demonstrated abnormal synaptic plasticity in the corticostriatal system, possibly related to the development of levodopa-induced dyskinesias (LID). We tested the hypothesis that LID in Parkinson's disease is associated with aberrant plasticity in the human motor cortex (M1). We employed the paired associative stimulation (PAS) protocol, an experimental intervention involving transcranial magnetic stimulation (TMS) and median nerve stimulation capable of producing long-term potentiation (LTP) like changes in the sensorimotor system in humans. We studied the more affected side of 16 moderately affected patients with Parkinson's disease (9 dyskinetic, 7 non-dyskinetic) and the dominant side of 9 age-matched healthy controls. Motor-evoked potential (MEP) amplitudes and cortical silent period (CSP) duration were measured at baseline before PAS and for up to 60 min (T0, T30 and T60) after PAS in abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. PAS significantly increased MEP size in controls (+74.8% of baseline at T30) but not in patients off medication (T30: +0.07% of baseline in the non-dyskinetic, +27% in the dyskinetic group). Levodopa restored the potentiation of MEP amplitudes by PAS in the non-dyskinetic group (T30: +64.9% of baseline MEP) but not in the dyskinetic group (T30: -9.2% of baseline). PAS prolonged CSP duration in controls. There was a trend towards prolongation of CSP in the non-dyskinetic group off medications but not in the dyskinetic group. Levodopa did not restore CSP prolongation by PAS in the dyskinetic group. Our findings suggest that LTP-like plasticity is deficient in Parkinson's disease off medications and is restored by levodopa in non-dyskinetic but not in dyskinetic patients. Abnormal synaptic plasticity in the motor cortex may play a role in the development of LID.

Aged↗

PubMed2002

Dissociating ocular dominance column development and ocular dominance plasticity: a neurotrophic model.

Recent experimental data indicate that both neurotrophic factors (NTFs) and intracortical inhibitory circuitry are implicated in the development and plasticity of ocular dominance columns. We extend a neurotrophic model of developmental synaptic plasticity, which previously failed to account correctly for the differences between monocular deprivation and binocular deprivation, and show that the inclusion of lateral cortical inhibition is indeed necessary in understanding the effects of visual deprivation in the model. In particular, we argue that monocular deprivation causes a differential shift in the balance between inhibition and excitation in cortical columns, down-regulating NTFs in deprived-eye columns and up-regulating NTFs in undeprived-eye columns; during binocular deprivation, however, no such shift occurs. We thus postulate that the response to visual deprivation is at the level of the cortical circuit, while the mechanisms of afferent segregation are at the molecular or cellular level. Such a dissociation is supported by recent experimental work challenging the assumption that columnar organisation develops in an activity-dependent, competitive fashion. Our extended model also questions recent attempts to distinguish between heterosynaptic and homosynaptic models of synaptic plasticity.

Animals↗

PubMed1999

MK-801 improves retention in aged rats: implications for altered neural plasticity in age-related memory deficits.

Alterations in N-methyl-d-aspartate receptor (NMDAR)-dependent synaptic plasticity, characteristic of aged rodents, may contribute to impaired memory with advanced age. The purpose of the current research was to examine whether NMDARs contribute to rapid forgetting on a spatial memory task. Aged (22-24 months) and adult (3-6 months) male Fischer 344 rats received 18 training trials, over a period of 3 to 4 h, on the spatial version of the Morris water maze. Immediately after training, a standard free-swim probe trial was administered to assess the acquisition of spatial bias, which was determined by the percent of time spent in the goal quadrant and the number of platform crossings. Rats then received injections of the noncompetitive NMDAR antagonist, (+)-10, 11-dihydro-5methyl-5H-dibenzo(a,b)cycloheptene-5,10 imine (MK-801, 0. 05 mg/kg, i.p.), or a vehicle injection of equal volume. Approximately 24 h later, rats were administered a second free-swim probe trial to assess retention of spatial bias. All age/drug groups exhibited a spatial bias on the acquisition probe, with adults generally outperforming the aged rats. On the retention probe, this spatial bias continued to be shown by adult rats, regardless of treatment. For the aged group, in contrast, only MK-801-injected rats maintained a spatial bias on the retention probe, suggesting that NMDAR activity may be involved in rapid forgetting during aging. Because blockade of NMDARs also may impair new learning, which may, in turn, protect previously stored information from retroactive interference, rats in a second experiment received post-training injections of scopolamine (0.05 mg/kg), a compound known to inhibit learning. However, scopolamine did not enhance retention in the aged group, consistent with the hypothesis that MK-801 influenced memory in aged rats through its actions on NMDAR-dependent synaptic plasticity.

Aging↗

PubMed2005

Pattern-dependent, simultaneous plasticity differentially transforms the input-output relationship of a feedforward circuit.

Memories are believed to be encoded by changes in the synaptic connections between neurons. Although many forms of synaptic plasticity have been identified, it remains unknown how such changes affect local circuits. Feedforward inhibitory networks are a common type of local circuitry and occur when principal neurons and their afferent inhibitory interneurons receive the same input. Using slices of cerebellar cortex, we explored how synaptic plasticity at multiple sites within a feedforward inhibitory network consisting of parallel fibers, interneurons, and Purkinje neurons alters the output of this circuit. We found that stimuli resembling baseline activity potentiated feedforward excitatory and simultaneously depressed feedforward inhibitory pathways. In contrast, stimuli resembling sensory-evoked patterns of firing potentiated both types of feedforward connections. These distinct forms of ensemble plasticity change the way Purkinje neurons subsequently respond to inputs. Such concerted changes in the circuitry of cerebellar cortex may contribute to certain forms of sensorimotor learning.

Animals↗

PubMed2006

Environment- and age-dependent plasticity of synaptic complexes in the mushroom bodies of honeybee queens.

Diversity in behavior plays a crucial role for the division of labor in insect societies. Social insects such as honeybees provide excellent model systems to investigate neuronal principles underlying behavioral plasticity. The two female castes, queens and workers, differ substantially in anatomy, physiology, aging and behavior. The different phenotypes are induced by environmental factors rather than genetic differences. Here we investigated environment- and age-dependent effects on the synaptic organization within higher order neuropils of the honeybee brain. Synaptic complexes (microglomeruli) in sensory-input regions of the mushroom bodies, prominent higher sensory integration centers, were analyzed quantitatively using fluorescent markers and confocal microscopy. Pre- and postsynaptic compartments of individual microglomeruli were labeled by anti-synapsin immunolabeling and f-actin detection with phalloidin in dendritic spines of mushroom-body intrinsic neurons. The results demonstrate that in queens the numbers of microglomeruli in the olfactory and visual input regions of the mushroom-body calyx are significantly lower than in workers. In queens raised in incubators, microglomeruli were affected by differences in pupal rearing temperature within the range of naturally occurring temperatures (32-36 degrees C). The highest numbers of microglomeruli developed at a lower temperature compared to workers (33.5 vs. 34.5 degrees C). We found a striking adult plasticity of microglomeruli numbers throughout the extended life-span of queens. Whereas microglomeruli in the olfactory lip increased with age ( approximately 55%), microglomeruli in the visual collar significantly decreased ( approximately 35%). We propose that developmental and adult plasticity of the synaptic circuitry in the mushroom-body calyx might underlie caste- and age-specific adaptations in behavior.

Animals↗

PubMed2005

Chronic intermittent ethanol exposure enhances NMDA-receptor-mediated synaptic responses and NMDA receptor expression in hippocampal CA1 region.

In previous studies, we found that chronic intermittent ethanol (CIE) treatment-a model of ethanol consumption in which animals are exposed to and withdrawn from intoxicating levels of ethanol on a daily basis-produces neuroadaptive changes in hippocampal area CA1 excitatory synaptic transmission and plasticity. Synaptic responses mediated by N-methyl-D-aspartate (NMDA) receptors are known to be sensitive to ethanol and could play an important role in the neuroadaptive changes induced by CIE treatment. To address this issue, we compared electrophysiological recordings of pharmacologically isolated NMDA-receptor-mediated field excitatory postsynaptic potentials (fEPSPs) in the CA1 region of hippocampal slices prepared from control rats and rats exposed to 2 weeks of CIE treatment administered by vapor inhalation. We found that fEPSPs induced by NMDA receptor activation were unaltered in slices prepared shortly after cessation of CIE treatment (i.e., < or = 1 day of withdrawal from CIE). However, following 7 days of withdrawal from CIE treatment, NMDA-receptor-mediated fEPSPs were augmented relative to age-matched controls. Western blot analysis of NMDA receptor subunit expression showed that, at 7 days of withdrawal, the level of protein for NR2A and NR2B subunits was elevated in the CA1 region of hippocampal slices from CIE-treated animals compared with slices from age-matched controls. These results are consistent with an involvement of NMDA-receptor-mediated synaptic responses in the neuroadaptive effects of CIE on hippocampal physiology and suggest that such changes may contribute to ethanol-induced changes in processes dependent on NMDA-receptor-mediated synaptic responses such as learning and memory, neural development, hyperexcitability and seizures, and neurotoxicity.

Animals↗

PubMed2006

Group I metabotropic glutamate receptors activate the p70S6 kinase via both mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK 1/2) signaling pathways in rat striatal and hippocampal synaptoneurosomes.

Group I metabotropic glutamate receptors (mGluRs) have been demonstrated to play a role in synaptic plasticity via a rapamycin-sensitive mRNA translation signaling pathway. Various growth factors can stimulate this pathway, leading to the phosphorylation and activation of mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that modulates the activity of several translation regulatory factors, such as p70S6 kinase. However, little is known about the cellular and molecular mechanisms that bring the plastic changes of synaptic transmission after stimulation of group I mGluRs. Here, we investigated the role of the mTOR-p70S6K and the ERK1/2-p70S6K pathways in rat striatal and hippocampal synaptoneurosomes after group I mGluR stimulation. Our findings show that (S)-3,5-dihydroxyphenylglycine (DHPG) increases significantly the activation of mTOR and p70S6K (Thr389, controlled by mTOR) in both brain areas. The mTOR activation is dose-dependent and requires the stimulation of mGluR1 subtype receptors as for the p70S6K activation observed in striatum and hippocampus. In addition, the p70S6K (Thr421/Ser424) activation via the ERK1/2 activation is increased and involved also mGluR1 receptors. These results demonstrate that group I mGluRs are coupled to mTOR-p70S6K and ERK1/2-p70S6K pathways in striatal and hippocampal synaptoneurosomes. The translational factor p70S6K could be involved in the group I mGluRs-modulated synaptic efficacy.

Animals↗

PubMed2005

Decreases in CaMKII activity trigger persistent potentiation of intrinsic excitability in spontaneously firing vestibular nucleus neurons.

Calcium/calmodulin-dependent protein kinase II (CaMKII) has been described as a biochemical switch that is turned on by increases in intracellular calcium to mediate synaptic plasticity. Here, we show that reductions in CaMKII activity trigger persistent increases in intrinsic excitability. In spontaneously firing vestibular nucleus neurons, CaMKII activity is near maximal, and blockade of CaMKII activity increases excitability by reducing BK-type calcium-activated potassium currents. Firing rate potentiation, a form of plasticity in which synaptic inhibition induces long-lasting increases in excitability, is occluded by prior blockade of CaMKII and blocked by addition of constitutively active CaMKII. Reductions in CaMKII activity are necessary and sufficient to induce firing rate potentiation and may contribute to motor learning in the vestibulo-ocular reflex.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2000

Roles of NMDA receptor activity and nitric oxide production in brain development.

The concept that neural activity is important for brain maturation has focused much research interest on the developmental role of the NMDA receptor, a key mediator of experience-dependent synaptic plasticity. However, a mechanism able to link spatial and temporal parameters of synaptic activity during development emerged as a necessary condition to explain how axons segregate into a common brain region and make specific synapses on neuronal sub-populations. To comply with this developmental constraint, it was proposed that nitric oxide (NO), or other substances having similar chemical and biological characteristics, could act as short-lived, activity-dependent spatial signals, able to stabilize active synapses by diffusing through a local volume of tissue. The present article addresses this issue, by reviewing the experimental evidence for a correlated role of the activity of the NMDA receptor and the production of NO in key steps of neural development. Evidence for such a functional coupling emerges not only concerning synaptogenesis and formation of neural maps, for which it was originally proposed, but also for some earlier phases of neurogenesis, such as neural cell proliferation and migration. Regarding synaptogenesis and neural map formation in some cases, there is so far no conclusive experimental evidence for a coupled functional role of NMDA receptor activation and NO production. Some technical problems related to the use of inhibitors of NO formation and of gene knockout animals are discussed. It is also suggested that other substances, known to act as spatial signals in adult synaptic plasticity, could have a role in developmental plasticity. Concerning the crucial developmental phase of neuronal survival or elimination through programmed cell death, the well-documented survival role related to NMDA receptor activation also starts to find evidence for a concomitant requirement of downstream NO production. On the basis of the reviewed literature, some of the major controversial issues are addressed and, in some cases, suggestions for possible future experiments are proposed.

Animals↗

PubMed2000

What is the function of receptor and membrane endocytosis at the postsynaptic neuron?

This paper explores the implications of certain new developments in cell biology upon neuroscience. Until recently it was thought that neurotransmitters and neuromodulators had only one function, which was to stimulate their specific receptors at the cell surface. From here on, all activity was supposed to be effected by postsynaptic cascades. The discovery that membrane components, particularly G-protein-linked receptors, are not static but are subject to a massive and complex process of continual endocytosis, processing in the endosome system and recycling back to the external membrane, raises the question of its functional significance. In addition, it has been found that many neuromodulators such as polypeptides have their main locus of action inside the postsynaptic neuron. This review covers the role of the endocytic mechanism on receptor desensitization and resensitization, synaptic reorganization and plasticity synaptic scaling and the possible repair of oxidative damage. The possible involvement of this system in Alzheimer's disease is discussed.

Animals↗

PubMed1996

Bidirectional plasticity expressed by GABAergic synapses in the neonatal rat hippocampus.

1. Activity-dependent plasticity of GABAergic synaptic transmission was investigated in neonatal rat hippocampal slices obtained between postnatal day (P) 2-10 using intracellular recording techniques. In all experiments, AMPA receptors were blocked by continual application of CNQX (10 microM). 2. Between P2 and P4, tetanic stimulation (TS) evoked NMDA receptor-dependent long-term depression of monosynaptic GABAA EPSPS (LTDGABAA). In contrast, when NMDA receptors were blocked by D-AP5 (50 microM), the same TS evoke long-term potentiation of GABAA EPSPS (LTPGABAA). 3. Between P6 and P10, TS failed to produce either LTP or LTD or hyperpolarizing monosynaptic GABAA IPSPS under the same recording conditions. However, when GABAergic potentials were rendered depolarizing (KCl-filled electrode) Ts induced either LTPGABAA or LTDGABAA in the presence or absence of D-AP5, respectively. 4. Both LTPGABAA and LTDGABAA were specific to the conditioned pathway and could be sequentially expressed at the same synapses. Potentiation of GABAergic synaptic efficacy was induced more easily following previous induction of LTDGABAA than in naive slices. 5. In conclusion, early in development, bidirectional synaptic plasticity is expressed by GABAA receptors and the activation (or not) of NMDA receptors determines the induction of either LTPGABAA or LTDGABAA.

Animals↗

PubMed1999

L-type voltage-gated calcium channels mediate NMDA-independent associative long-term potentiation at thalamic input synapses to the amygdala.

Long-term potentiation (LTP) in the amygdala is a leading candidate mechanism to explain fear conditioning, a prominent model of emotional memory. LTP occurs in the pathway from the auditory thalamus to the lateral amygdala, and during fear conditioning LTP-like changes occur in the synapses of this pathway. Nevertheless, LTP has not been investigated in the thalamoamygdala pathway using in vitro recordings; hence little is known about the underlying mechanisms. We therefore examined thalamoamygdala LTP in vitro using visualized whole-cell patch recording. LTP at these synapses was dependent on postsynaptic calcium entry, similar to synaptic plasticity in other regions of the brain. However, unlike many forms of synaptic plasticity, thalamoamygdala LTP was independent of NMDA receptors, despite their presence at these synapses, and instead was dependent on L-type voltage-gated calcium channels. This was true when LTP was induced by pairing presynaptic activity with either action potentials or constant depolarization in the postsynaptic cell. In addition, the LTP was associative, in that it required concurrent pre- and postsynaptic activity, and it was synapse specific. Thus, although this LTP is different from that described at other synapses in the brain, it is nonetheless well suited to mediate classical fear conditioning.

Afferent Pathways↗