SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
In this issue of Neuron, record from synaptically coupled pairs of CA3 neurons to closely examine the induction of synaptic depression at a small number of identified synapses. The authors provide convincing evidence that the activation history of a synapse determines both the ability of a synapse to depress and the mechanism of depression.
Paired-pulse plasticity is typically used to study the mechanisms underlying synaptic transmission and modulation. An important question relates to whether, under physiological conditions in which various opposing synaptic properties are acting in parallel, the net effect is facilitatory or depressive, that is, whether cells further or closer to threshold. For example, does the net sum of paired-pulse facilitation (PPF) of excitatory postsynaptic potentials (EPSPs), paired-pulse depression (PPD) of inhibitory postsynaptic potentials (IPSPs), and the hyperpolarizing slow IPSP result in depression or facilitation? Here we examine how different time-dependent properties act in parallel and examine the contribution of gamma-aminobutyric acid-B (GABAB) receptors that mediate two opposing processes, the slow IPSP and PPD of the fast IPSP. Using intracellular recordings from rat CA3 hippocampal neurons and L-II/III auditory cortex neurons, we examined the postsynaptic responses to paired-pulse stimulation (with intervals between 50 and 400 ms) of the Schaffer collaterals and white matter, respectively. Changes in the amplitude, time-to-peak (TTP), and slope of each EPSP were analyzed before and after application of the GABAB antagonist CGP-55845. In both CA3 and L-II/III neurons the peak amplitude of the second EPSP was generally depressed (further from threshold) compared with the first at the longer intervals; however, these EPSPs were generally broader and exhibited a longer TTP that could result in facilitation by enhancing temporal summation. At the short intervals CA3 neurons exhibited facilitation of the peak EPSP amplitude in the absence and presence of CGP-55845. In contrast, on average L-II/III cells did not exhibit facilitation at any interval, in the absence or presence of CGP-55845. CGP-55845 generally "erased" short-term plasticity, equalizing the peak amplitude and TTP of the first and second EPSPs at longer intervals in the hippocampus and auditory cortex. These results show that it is necessary to consider all time-dependent properties to determine whether facilitation or depression will dominate under intact pharmacological conditions. Furthermore our results suggest that GABAB-dependent properties may be the major contributor to short-term plasticity on the time scale of a few hundred milliseconds and are consistent with the hypothesis that the balance of different time-dependent processes can modulate the state of networks in a complex manner and could contribute to the generation of temporally sensitive neural responses.
Two neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are able to produce a long-lasting enhancement of synaptic transmission in the hippocampus. Unlike other forms of plasticity, neurotrophin-induced plasticity exhibited an immediate requirement for protein synthesis. Plasticity in rat hippocampal slices in which the synaptic neuropil was isolated from the principal cell bodies also required early protein synthesis. Thus, the neurotrophins may stimulate the synthesis of proteins in either axonal or dendritic compartments, allowing synapses to exert local control over the complement of proteins expressed at individual synaptic sites.
Recent experiments indicate that modification of synaptic strength may involve rapid regulation of vesicular traffic on the postsynaptic side of the synapse. The specific vesicular trafficking route taken by postsynaptic receptors appears to depend on the stimulus.
The past few decades have seen an explosion in our understanding of the molecular basis of learning and memory. The majority of these studies in mammals focused on post-synaptic signal transduction cascades involved in post-synaptic long-lasting plasticity. Until recently, relatively little work examined the role of presynaptic proteins in learning and memory in complex systems. The synaptic cleft figuratively represents a "great divide" between our knowledge of post- versus presynaptic involvement in learning and memory. While great strides have been made in our understanding of presynaptic proteins, we know very little of how presynaptically expressed forms of short- and long-term plasticity participate in information processing and storage. The paucity of cognitive behavioral research in the area of presynaptic proteins, however, is in stark contrast to the plethora of information concerning presynaptic protein involvement in neurotransmitter release, in modulation of release, and in both short- and long-term forms of presynaptic plasticity. It is now of great interest to begin to link the extensive literature on presynaptic proteins and presynaptic plasticity to cognitive behavior. In the future there is great promise with these approaches for identifying new targets in the treatment of cognitive disorders. This review article briefly surveys current knowledge on the role of presynaptic proteins in learning and memory in mammals and suggests future directions in learning and memory research on the presynaptic rim of the "great divide."
Long-term changes in the synaptic efficacy of corticostriatal synapses are believed to be important for regulating the excitatory input to the basal ganglia, and hence for motor learning and certain forms of cognition. Previous reports have suggested that long-term depression (LTD) is the predominant form of plasticity at corticostriatal synapses. However, we report here that tetanic stimulation of the white matter can readily induce long-term potentiation (LTP) at corticostriatal synapses in a sagittal slice preparation. Furthermore, we find that corticostriatal LTP is obtained in the absence of pharmacological manipulation, and is dependent on NMDA receptor activation. In contrast, LTD is rarely observed following tetanic stimulation of the white matter, but in fact requires direct stimulation within the striatum. This striatally induced depression is blocked by both D1 and D2 dopamine receptor antagonists and by NMDA receptor blockade. Pairing of striatal stimulation with tetanic stimulation of the white matter does not prevent the induction, but significantly enhances the magnitude of LTP at corticostriatal synapses. We suggest that the corticostriatal depression reported here most likely involves the recruitment of local striatal circuits and dopaminergic inputs, and thus might explain the predominance of LTD previously reported. Our observation that it is indeed possible to induce LTP at corticostriatal synapses under physiological conditions in vitro has implications for the normal function and control of the basal ganglia in motor learning and cognition.
A widely studied example of vertebrate plasticity is LTP (long-term potentiation), the persistent synaptic enhancement that follows a brief period of coinciding pre- and post-synaptic activity. During LTP, different kinases, including CaMKII (calcium/calmodulin-dependent protein kinase II) and protein kinase A, become activated and play critical roles in induction and maintenance of enhanced transmission. Biochemical analyses have revealed several regulated phosphorylation sites in the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunits, GluR1 and GluR4. The regulated insertion of these receptors is a key event in the induction of LTP. Here, we discuss the phosphorylation of GluR1 and GluR4 and its role in receptor delivery and neuronal plasticity.
Using morphometric methods, the synaptic architectonics of the neocortex molecular layer was studied in nine patients with brain tumours and intracranial hypertension of various severity which determined the degree of cerebral hypoxia. It has been demonstrated that the synapses of the human brain are characterized by marked plastic properties manifested predominantly by the hypertrophy of the active zones of the contact and the formation of the interneuronal links. The reorganization of the synaptic architectonics plays a significant compensatory role in human cerebral functions under hypoxia.
Use-dependent changes of synaptic transmission are thought to depend on the evaluation of temporal correlations between pre- and postsynaptic excitatory activity. Previous studies have demonstrated long-term potentiation (LTP) in layer V pyramidal cells after coincident pairing of presynaptic excitatory input with postsynaptic depolarizations, evoking backpropagating action potentials (BAPs). Here we paired excitatory layer II input with somatic hyperpolarization, which blocked BAPs in layer V pyramidal cells of rat visual cortex and induced reliable long-term depression (LTD). Upon cholinergic receptor activation, this BAP-independent protocol also induced LTP, which was not dependent on N-methyl-d-aspartate receptor activation, but blocked by metabotropic glutamate receptor (mGluR) antagonists.
1. The role of actin microfilaments in synaptic transmission was tested by monitoring spontaneous and evoked transmitter release from developing neuromuscular synapses in Xenopus nerve-muscle cultures, using whole-cell recording of synaptic currents in the absence and presence of microfilament-disrupting agents cytochalasins B and D. 2. Treatment with cytochalasins resulted in disruption of microfilament networks in the growth cone and the presynaptic nerve terminal of spinal neurons in Xenopus nerve-muscle cultures, as revealed by rhodamine-phalloidin staining. 3. The same cytochalasin treatment did not significantly affect the spontaneous or evoked synaptic currents during low-frequency stimulation at 0.05 Hz in these Xenopus cultures. Synaptic depression induced by high-frequency (5 Hz) stimulation, however, was reduced by this treatment. Paired-pulse facilitation for short interpulse intervals was also increased by the treatment. 4. These results indicate that disruption of microfilaments alters short-term changes in transmitter release induced by repetitive activity, without affecting normal synaptic transmission at low frequency. 5. Our results support the notion that actin microfilaments impose a barrier for mobilization of synaptic vesicles from the reserve pool, but do not affect the exocytosis of immediately available synaptic vesicles at the active zone.
Sensitization produced by intracellular administration of a specific protein kinase C inhibitor chelerythrine selectively inhibits synaptic facilitation in the response of LPl1 neurons to tactile sensory stimulation of snail head. Synaptic facilitation in the response to chemical stimulation of the head or tactile stimulation of the foot did not differ from that observed in neurons of control sensitized animals. Our findings suggest that protein kinase C plays a key role in the induction of long-term genetic regulation of sensory input in command neurons from mechanoreceptors on the head.
Direction selectivity (DS) of simple cells in the primary visual cortex was recently suggested to arise from short-term synaptic depression in thalamocortical afferents (Chance F, Nelson S, Abbott L (1998), J. Neuroscience 18(12): 4785-4799). In the model, two groups of afferents with spatially displaced receptive fields project through either depressing and non-depressing synapses onto the V1 cell. The degree of synaptic depression determines the temporal phase advance of the response to drifting gratings. We show that the spatial displacement and the appropriate degree of synaptic depression required for DS can develop within an unbiased input scenario by means of temporally asymmetric spike-timing dependent plasticity (STDP) which modifies both the synaptic strength and the degree of synaptic depression. Moving stimuli of random velocities and directions break any initial receptive field symmetry and produce DS. Frequency tuning curves and subthreshold membrane potentials akin to those measured for non-directional simple cells are thereby changed into those measured for directional cells. If STDP is such that down-regulation dominates up-regulation the overall synaptic strength adapts in a self-organizing way such that eventually the postsynaptic response for the non-preferred direction becomes subthreshold. To prevent unlearning of the acquired DS by randomly changing stimulus directions an additional learning threshold is necessary. To further protect the development of the simple cell properties against noise in the stimulus, asynchronous and irregular synaptic inputs are required.
Lithium, a small cation, has been used in the treatment of bipolar disorders since its introduction in the 1950s by John Cade. Extensive research on the mechanism of action of lithium has revealed several possible targets. For some time, the most widely accepted action of lithium was its inhibitory effect on the synthesis of inositol, resulting in depletion of inositol with profound effects on neuronal signal transduction pathways. However, several studies show that some effects of lithium are not mediated through inositol depletion. Recent findings demonstrate that lithium directly inhibits, in a non-competitive fashion, the activity of glycogen synthase kinase (GSK)-3beta, a serine/threonine kinase highly expressed in the central nervous system. Interestingly, inhibition of GSK-3beta has been shown to regulate neuronal plasticity by inducing axonal remodelling and increasing the levels of synaptic proteins. These findings raise the possibility for developing new therapeutic approaches for the treatment of bipolar disorders.
The effects of histamine on baseline synaptic transmission and long-term potentiation (LTP) were investigated in the CA1 region of rat hippocampal slices. Bath applied histamine reversibly and dose-dependently increased the amplitude of extracellularly recorded population spikes in the concentration range 0.1-100 microM by a maximum of 40%. At higher concentrations (10-100 microM) histamine also caused a small depression of field excitatory postsynaptic potentials (fEPSPs) of approx 10%. The effect of histamine on population spikes was found to be mediated through histamine H2 receptors. Histamine (10-100 microM) was found to produce a statistically significant LTP of fEPSPs when combined with a weak tetanus (0.25 sec, 50 Hz). Histamine H1 (mepyramine, 1 microM) and H2 (cimetidine, 50 microM) receptor antagonists did not block this enhanced potentiation. In addition, histamine (10-100 microM) enhanced the late portion of the response produced by pressure ejection of glutamate receptor agonist N-methyl-D-aspartate into the slice, as recorded extracellularly or intracellularly. This effect of histamine was only apparent when large NMDA responses were obtained, using a high pipette concentration of NMDA (1 mM). In the presence of histamine H1 and H2 antagonists, potassium channel blockers or blockade of inhibition, this enhancement could still be observed. We conclude that histamine facilitated the induction of LTP, most likely by acting directly at the NMDA receptor.
Alzheimer's disease can be considered a protein misfolding disease. In particular, inappropriate processing of a proteolytic fragment of amyloid precursor protein, amyloid beta-protein (Abeta), in early stages of Alzheimer's disease may lead to stabilization of small oligomers that are highly mobile and have a potential to be extremely toxic assemblies. Recently, the importance of such soluble species of Abeta in triggering synaptic dysfunction, long before neuronal loss occurs, has become apparent. Animal models have revealed that plasticity of hippocampal excitatory synaptic transmission is relatively selectively vulnerable to Abeta both in vitro and in vivo. This review focuses on the mechanisms of Abeta inhibition of long-term potentiation at synapses in the rodent hippocampus from two complimentary perspectives. Firstly, we examine evidence that the synaptic activity of this peptide resides primarily in oligomeric rather than monomeric or fibrillar Abeta species. Secondly, the importance of different oxidative/nitrosative stress-linked cascades including JNK, p38 MAPK and NADPH oxidase/iNOS-generated reactive oxygen/nitrogen free radicals in mediating the inhibition of LTP by Abeta is emphasised. These mechanistic studies provide a plausible explanation for the sensitivity of hippocampus-dependent memory to impairment in the early preclinical stages of Alzheimer's disease.
Long-term potentiation (LTP) and long-term depression of synaptic transmission in the hippocampus are widely studied models of learning and memory processes. The role of ATP-regulated K+ channels (K(ATP)+ channels), which are abundant in the brain, has not yet been studied in long-term potentiation or long-term depression. We investigated whether K(ATP)+ channel inhibition by the highly selective K(ATP)+-channel blocker 1-[[5-[2-(5-tert-butyl-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea (HMR-1372), a novel putative class III antiarrhythmic, affects long-term potentiation or the long-term depression induced by 3,5-dihydroxyphenylglycine (30 microM) in submerged rat hippocampal slices. HMR-1372 (10 microM) did not affect basal synaptic transmission, paired pulse inhibition, long-term depression or long-term potentiation elicited by a weak (weak long-term potentiation) tetanus, but significantly amplified the long-term efficacy of long-term potentiation elicited by a strong tetanus (strong long-term potentiation). The K(ATP)+-channel inhibitor glibenclamide (20 microM) also ameliorated only strong long-term potentiation. Our data suggest that K(ATP)+ channels are activated during or after induction of long-term potentiation and play a role in controlling synaptic excitability.
Experimental studies have revealed conspicuous short-term facilitation and depression that are expressed differentially at distinct classes of cortical synapses. To explore computational implications of synaptic dynamics, we investigated transmission of complex spike trains through a stochastic model of cortical synapse endowed with short-term facilitation and vesicle depletion. Inputs to the synapse model were either real spike train data recorded from the visual and prefrontal cortices of behaving monkeys, or were generated numerically with prescribed temporal statistics. We tested the hypothesis that short-term facilitation could enable synapses to filter out single spikes and favor bursts of action potentials. We found that the ratio between release probabilities for a burst spike and an isolated spike grows monotonically with increasing number of spikes per burst, and with increasing interval between isolated spikes. Burst detection is optimal when the facilitation time constant matches the average burst duration. Using fractal-like spike patterns characterized by long-term power-law temporal correlations and similar to those seen in sensory neurons, we found that facilitation increases correlation at short time scales. In contrast, depression leads to a dramatic reduction in temporal correlations at all time scales, and to a flat ('whitened') power spectrum, thereby decorrelating natural input signals.
Neuronal plasticity is now known to be very important in the adult, both in the formation of new synaptic connections and of new neurones (neurogenesis) and of glial cells. However, old age and stress can inhibit this plasticity and lead to cerebral atrophy. The time course of changes in neuronal plasticity involves, in the first milliseconds to seconds, changes in synaptic strength (long term potentialisation, LTP, or long term depression, LTD), then, over minutes to hours, changes in the number of synaptic connections (linked to changes in neurotrophic factors), and over weeks to months, to changes in neuronal reconfiguration. These changes in brain systems are particularly targeted in psychiatric disorders to the areas which are sensitive to stress and play roles in memory and emotion (hippocampus, amygdala and prefrontal cortex). The discovery and development of drugs modifying neuronal plasticity and neurotrophins production has been a priority for Servier research for the last ten years; Servier has a clinically effective antidepressant, tianeptine (Stablon), with a favourable side effect profile, but which does not inhibit the uptake of serotonin, or other monoamines. However, this drug can reverse the deleterious effects of stress on neuronal plasticity, thereby acting on the causes of psychiatric disorders. Furthermore, a new research area is being investigated - facilitation of AMPA receptors, favouring the production of neurotrophic factors.