Climbing fiber synaptic plasticity and modifications in Purkinje cell excitability.
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Action Potentials↗
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Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome.
Loss-of-function mutations or abnormal expression of the X-linked gene encoding methyl CpG binding protein 2 (MeCP2) cause a spectrum of postnatal neurodevelopmental disorders including Rett syndrome (RTT), nonsyndromic mental retardation, learning disability, and autism. Mice expressing a truncated allele of Mecp2 (Mecp2(308)) reproduce the motor and social behavior abnormalities of RTT; however, it is not known whether learning deficits are present in these animals. We investigated learning and memory, neuronal morphology, and synaptic function in Mecp2(308) mice. Hippocampus-dependent spatial memory, contextual fear memory, and social memory were significantly impaired in Mecp2(308) mutant males (Mecp2(308/Y)). The morphology of dendritic arborizations, the biochemical composition of synaptosomes and postsynaptic densities, and brain-derived neurotrophic factor expression were not altered in these mice. However, reduced postsynaptic density cross-sectional length was identified in asymmetric synapses of area CA1 of the hippocampus. In the hippocampus of symptomatic Mecp2(308/Y) mice, Schaffer-collateral synapses exhibited enhanced basal synaptic transmission and decreased paired-pulse facilitation, suggesting that neurotransmitter release was enhanced. Schaffer-collateral long-term potentiation (LTP) was impaired. LTP was also reduced in the motor and sensory regions of the neocortex. Finally, very early symptomatic Mecp2(308/Y) mice had increased basal synaptic transmission and deficits in the induction of long-term depression. These data demonstrate a requirement for MeCP2 in learning and memory and suggest that functional and ultrastructural synaptic dysfunction is an early event in the pathogenesis of RTT.
Animals↗
Signaling between glia and neurons: focus on synaptic plasticity.
Glial cells are now emerging from the shadows cast by their more excitable CNS counterparts. Within the developing nervous system, astrocytes and Schwann cells actively help to promote synapse formation and function, and have even been implicated in synapse elimination. In the adult brain, astrocytes respond to synaptic activity by releasing transmitters that modulate synaptic activity. Thus, glia are active participants in brain function. Many questions remain about the identity of glial-neuronal signals and their significance.
Animals↗
Repeated electroconvulsive stimulation impairs synaptic plasticity in the dentate gyrus in vivo but has no effect in CA1 in vitro.
Repeated electroconvulsive stimulation (ECS) spaced at 48 h intervals significantly increased the synaptic response in the dentate gyrus in vivo, as measured by input/output curves, and reduced the degree of long-term potentiation (LTP) obtained following high frequency stimulation. An identical course of ECS had no effect on synaptic responses recorded in the stratum radiatum of CA1 in vitro and did not impair high frequency-induced LTP. These results suggest that either ECS has a selective effect on the sub-fields of the hippocampus or that in vitro recording techniques are unsuitable for detecting the increase in synaptic efficacy produced by the treatments.
Animals↗
Rate, timing, and cooperativity jointly determine cortical synaptic plasticity.
Cortical long-term plasticity depends on firing rate, spike timing, and cooperativity among inputs, but how these factors interact during realistic patterns of activity is unknown. Here we monitored plasticity while systematically varying the rate, spike timing, and number of coincident afferents. These experiments demonstrate a novel form of cooperativity operating even when postsynaptic firing is evoked by current injection, and reveal a complex dependence of LTP and LTD on rate and timing. Based on these data, we constructed and tested three quantitative models of cortical plasticity. One of these models, in which spike-timing relationships causing LTP "win" out over those favoring LTD, closely fits the data and accurately predicts the build-up of plasticity during random firing. This provides a quantitative framework for predicting the impact of in vivo firing patterns on synaptic strength.
Action Potentials↗
Antidepressants and synaptic plasticity: a hypothesis.
The assumption is introduced that there are two types of adaptive responses in central neurons in response to significantly changed circuit activity. Morphological synaptic modifications and synapse turnover are thought to be involved in both of these responses, in such a way that in the first case they are to restore the circuit activity level as it was in the past, and in the second case they are to switch it to a new pattern. The events eliciting synaptogenesis are proposed to be different in these instances. The role of compensatory extrasynaptic receptors insertion and preferential insertion of synaptic receptors induced by enhanced presynaptic activity are discussed. The hypothesis as to how these two adaptive responses come into action during depression and antidepressant treatment is then proposed.
Adaptation, Physiological↗
Synaptic plasticity in kindling.
Kindling is an experimental model of epilepsy resulting from progressive activity-dependent changes in neuronal structure and function. During kindling, pathologic changes occur at various levels of organization of the nervous system, ranging from altered gene-expression in individual neurons to the loss of specific neuronal populations and the rearrangement of synaptic connections. This chapter summarizes recent findings about the long-lasting (plastic) nature of the alterations at the level of single neurons with emphasis on the role of altered excitatory and inhibitory amino acid receptors. The modified synaptic ligand-gated ion channels (i.e., "epileptic receptors") may ultimately be responsible for the kindling epileptogenesis.
Animals↗
Serine proteases regulating synaptic plasticity.
A number of molecules have been postulated to be involved in long-term potentiation, an experimental model for learning and short-term memory. Although the molecular mechanisms of the long-term potentiation have been considerably well understood, it is not yet known why and how real memory can last very long with outstanding stability. A mechanical change of synaptic morphology at acquisition, consolidation and retention of memory is hypothesized to explain long-lasting memory. Changes in the synaptic morphology may be due, at least in part, to local extracellular proteolysis of cell adhesion and extracellular matrix molecules. Some extracellular serine proteases of the Clan PA family may modulate synaptic adhesion and associate with long-term potentiation and learning behavior. In the present review, candidate proteases that are involved in the hippocampal memory are overviewed.
Animals↗
Modulation of seizures and synaptic plasticity by adenosinergic receptors in an experimental model of temporal lobe epilepsy induced by pilocarpine in rats.
PURPOSE: Adenosine is a major negative neuromodulator of synaptic activity in the central nervous system and can exert anticonvulsant and neuroprotective effects in many experimental models of epilepsy. Extracellular adenosine can be formed by a membrane-anchored enzyme ecto-5'-nucleotidase. The purposes of this study were to characterize the role of adenosine receptors in modulating status epilepticus (SE) induced by pilocarpine and evaluate its neuroprotective action. Ecto-5'-nucleotidase activity was studied during the different phases of pilocarpine-induced epilepsy in rats. METHODS: Adult rats were pretreated with different adenosinergic agents to evaluate the latency and incidence of SE induced by pilocarpine in rats. The neuroprotective effect also was evaluated. RESULTS: A proconvulsant effect was observed with DPCPX and DMPX that reduced the latency of SE in almost all rats. Pretreatment with the MRS 1220 did not alter the incidence of SE but reduced the latency to develop SE. An anticonvulsant and neuroprotective effect was detected with R-PIA. Rats pretreated with R-PIA had a decreased number of apoptotic cells in the hippocampus, whereas pretreatment with DPCPX did not modify the hippocampal damage. An intensification of neuronal death was observed in the dentate gyrus and CA3 when rats were pretreated with DMPX. MRS-1220 did not modify the number of apoptotic cells in the hippocampus. An increase in the ecto-5 -nucleotidase staining was detected in the hippocampus during silent and chronic phases. CONCLUSIONS: The present data show that adenosine released during pilocarpine-induced SE via A1-receptor stimulation can exhibit neuroprotective and anticonvulsant roles. Similar effects could also be inferred with A2a and A3 adenosinergic agents, but further experiments are necessary to confirm their roles. Ecto-5 -nucleotidase activity during silent and chronic phases might have a role in blocking spontaneous seizures by production of inhibitory neuromodulator adenosine, besides taking part in the mechanism that controls sprouting.
5'-Nucleotidase↗
Plasticity of synaptic transmission in autonomic ganglia.
Synaptic plasticity is a term that describes long-lasting changes in the efficacy of synaptic transmission resulting from certain patterned activities of the presynaptic nerve. One form of synaptic plasticity, long-term potentiation (LTP), is an activity-dependent marked increase in synaptic efficacy that has been extensively studied in various regions of the central nervous system, particularly the hippocampus, where LTP is widely believed to be a cellular correlate of learning and memory. A similar phenomenon has been identified in sympathetic ganglia even before Bliss and Lomo coined the term LTP in 1973. Ganglionic LTP (gLTP) of the nicotinic pathway is a similarly long-lasting increase in synaptic effectiveness that can be induced in ganglia following a brief train of relatively high frequency stimulation (HFS) of the preganglionic nerve. Remarkably similar to the LTP of the hippocampus, gLTP has been demonstrated in autonomic ganglia from a number of vertebrates including mammalian, amphibian and avian species. Several other forms of long-lasting increases in synaptic effectiveness have been demonstrated in sympathetic ganglia following exposure to adrenergic agonists, neuroactive peptides and cyclic nucleotides and even after a challenge by an antigen. The main emphasis of this review, however, will be on the activity-dependent gLTP of the mammalian sympathetic ganglia, in particular the superior cervical ganglion of the rat. Since the last, excellent and comprehensive review of this ganglionic function by Briggs in 1995, important discoveries about the mechanisms of induction and maintenance of gLTP have been reported, including the finding that the response is uniquely dependent on serotonin for both the induction phase and maintenance phase. These new advances will be discussed in depth in this review.
Animals↗
Associative synaptic plasticity in hippocampus and visual cortex: cellular mechanisms and functional implications.
Synchronous pre- and postsynaptic neuronal activity results in long-term potentiation (LTP) of excitatory synaptic transmission in the hippocampus and the neocortex. Induction of this form of potentiation requires calcium influx mediated by NMDA receptors. Experimental evidence is reviewed for induction of long-term depression (LTD) of synaptic transmission in the hippocampus in vitro and neocortical neurons in vivo, when the discharge of the postsynaptic neuron is temporally decorrelated from the presynaptic stimulation. Homosynaptic LTD induced by low frequency tetani in the hippocampus in vitro requires NMDA receptor activation and a moderate calcium influx. The role of postsynaptic calcium as a key parameter in the encoding of temporal contiguity of neural activity and its possible implications in the formation of engrams during specific learning tasks are discussed.
Animals↗
Analysis of NMDA receptor mediated synaptic plasticity using gene targeting: roles of Fyn and FAK non-receptor tyrosine kinases.
The NMDA receptor activates a biochemical pathway that regulates long-term changes in synaptic strength. A combination of pharmacological and gene-knockout approaches shows that the postsynaptics signalling cascade initiated by the NMDA receptor involves Fyn tyrosine kinase. We found that Fyn phosphorylates the NMDA receptor and proteins associated with the receptor and proteins associated with the receptor. The interaction of the NMDA receptor with postsynaptic signalling proteins is likely to initiate changes in synaptic strength that contribute to learning and memory.
Animals↗
Non-involvement of the redox site of NMDA receptors in bidirectional synaptic plasticity in the CA1 area of the rat hippocampus in vitro.
We have examined the effects of the redox reagent 5,5'-dithiobis-2-nitrobenzoic acid (DTNB) on synaptic potentials recorded extracellularly from the CA1 area in hippocampal slices following low frequency stimulation (LFS) and tetanic stimulation (TS). Application of DTNB (200 microM) neither changed synaptic responses, nor prevented the expression of TS-induced long-term potentiation of synaptic responses and their depotentiation by LFS. Conversely, in naive slices, LFS still induced long-term depression of synaptic responses following application of DTNB. This depression could be subsequently reversed with a TS. It is concluded that the redox state of N-methyl-D-aspartate receptors does not affect the expression of long-term potentiation and depression of synaptic responses.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
Adenosine gates synaptic plasticity at hippocampal mossy fiber synapses.
The release properties of synapses in the central nervous system vary greatly, not only across anatomically distinct types of synapses but also among the same class of synapse. This variation manifests itself in large part by differences in the probability of transmitter release, which affects such activity-dependent presynaptic forms of plasticity as paired-pulse facilitation and frequency facilitation. This heterogeneity in presynaptic function reflects differences in the intrinsic properties of the synaptic terminal and the activation of presynaptic neurotransmitter receptors. Here we show that the unique presynaptic properties of the hippocampal mossy fiber synapse are largely imparted onto the synapse by the continuous local action of extracellular adenosine at presynaptic A1 adenosine receptors, which maintains a low basal probability of transmitter release.
Adenosine↗
Roles of serine/threonine phosphatases in hippocampal synaptic plasticity.
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Animals↗
Excitatory amino acid neurotransmission: NMDA receptors and Hebb-type synaptic plasticity.
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Amino Acids↗
Myelination: an overlooked mechanism of synaptic plasticity?
Myelination of the brain continues through childhood into adolescence and early adulthood--the question is, Why? Two new articles provide intriguing evidence that myelination may be an underappreciated mechanism of activity-dependent nervous system plasticity: one study reported increased myelination associated with extensive piano playing, another indicated that rats have increased myelination of the corpus callosum when raised in environments providing increased social interaction and cognitive stimulation. These articles make it clear that activity-dependent effects on myelination cannot be considered strictly a developmental event. They raise the question of whether myelination is an overlooked mechanism of activity-dependent plasticity, extending in humans until at least age 30. It has been argued that regulating the speed of conduction across long fiber tracts would have a major influence on synaptic response, by coordinating the timing of afferent input to maximize temporal summation. The increase in synaptic amplitude could be as large as neurotransmitter-based mechanisms of plasticity, such as LTP. These new findings raise a larger question: How did the oligodendrocytes know they were practicing the piano or that their environment was socially complex?
Animals↗
Energetics and oxidative stress in synaptic plasticity and neurodegenerative disorders.
As in other cells, neurons use adenosine triphosphate (ATP) as an energy source to drive biochemical processes involved in various cell functions, and produce reactive oxygen species (ROS) as "by products" of oxidative phosphorylation. However, the electrical excitability and structural and synaptic complexity of neurons present unusual demands upon cellular systems that produce or respond to ATP and ROS. Mitochondria in axons and presynaptic terminals provide sources of ATP to drive the ion pumps that are concentrated in these structures to rapidly restore ion gradients following depolarization and neurotransmitter release. Mitochondria may also play important roles in the regulation of synaptic function because of their ability to regulate calcium levels and ROS production. ROS generated in response to synaptic activity are now known to contribute to the regulation of long-term structural and functional changes in neurons, and the best-known example is the nitric oxide radical. The high-energy demands of synapses, together with their high levels of ROS production, place them at risk during conditions of increased stress, which occur in aging, neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, and after acute traumatic and ischemic insults. Energy depletion and/or increased oxidative damage to various synaptic proteins can result in a local dysregulation of calcium homeostasis and synaptic degeneration. Accordingly, recent studies have shown that dietary and pharmacological manipulations that improve energy efficiency and reduce oxyradical production can prevent synaptic degeneration and neuronal death in experimental models of neurodegenerative disorders. A better understanding of the molecular control of subcellular energy production and utilization, and of the functional relationships between energy metabolism, ion homeostasis, and cytoskeletal and vesicular dynamics, will provide novel insight into mechanisms of neuronal plasticity and disease.
Adenosine Triphosphate↗