热性癫痫发作大鼠海马齿状回外侧支的可塑性和再可塑性

热性癫痫发作是儿童常见病,能损害认知功能,而突触可塑性和再可塑性(metaplasticity)是维系大脑认知功能的重要神经基础.本文通过脑片灌流和细胞外场电位记录术研究了热性癫痫发作大鼠海马齿状回外侧支的突触可塑性和再可塑性.制作对照组和热性癫痫发作组大鼠的脑切片后,记录电极置于齿状回外侧支的外分子层获取兴奋性突触后...     

Drugging the methylome: DNA methylation and memory

Over the past decade, since epigenetic mechanisms were first implicated in memory formation and synaptic plasticity, dynamic DNA methylation reactions have been identified as integral to long-term memory formation, maintenance, and recall. This review incorporates various new findings that DNA methylation mechanisms are important regulators of non-Hebbian plasticity mechanisms, suggesting that these epigenetic mechanisms are a fundamental link between synaptic plasticity and metaplasticity. Because the field of neuroepigenetics is so young and the biochemical tools necessary to probe gene-specific questions are just now being developed and used, this review also speculates about the direction and potential of therapeutics that target epigenetic mechanisms in the central nervous system and the unique pharmacokinetic and pharmacodynamic properties that epigenetic therapies may possess. Mapping the dynamics of the epigenome in response to experiential learning, even a single epigenetic mark in isolation, remains a significant technical and bioinformatic hurdle facing the field, but will be necessary to identify changes to the methylome that govern memory-associated gene expression and effectively drug the epigenome.     

The dual role of the extracellular matrix in synaptic plasticity and homeostasis

Recent studies have deepened our understanding of multiple mechanisms by which extracellular matrix (ECM) molecules regulate various aspects of synaptic plasticity and have strengthened a link between the ECM and learning and memory. New findings also support the view that the ECM is important for homeostatic processes, such as scaling of synaptic responses, metaplasticity and stabilization of synaptic connectivity. Activity-dependent modification of the ECM affects the formation of dendritic filopodia and the growth of dendritic spines. Thus, the ECM has a dual role as a promoter of structural and functional plasticity and as a degradable stabilizer of neural microcircuits. Both of these aspects are likely to be important for mental health.     

Glial tumor necrosis factor alpha (TNFα) generates metaplastic inhibition of spinal learning

Injury-induced overexpression of tumor necrosis factor alpha (TNFα) in the spinal cord can induce chronic neuroinflammation and excitotoxicity that ultimately undermines functional recovery. Here we investigate how TNFα might also act to upset spinal function by modulating spinal plasticity. Using a model of instrumental learning in the injured spinal cord, we have previously shown that peripheral intermittent stimulation can produce a plastic change in spinal plasticity (metaplasticity), resulting in the prolonged inhibition of spinal learning. We hypothesized that spinal metaplasticity may be mediated by TNFα. We found that intermittent stimulation increased protein levels in the spinal cord. Using intrathecal pharmacological manipulations, we showed TNFα to be both necessary and sufficient for the long-term inhibition of a spinal instrumental learning task. These effects were found to be dependent on glial production of TNFα and involved downstream alterations in calcium-permeable AMPA receptors. These findings suggest a crucial role for glial TNFα in undermining spinal learning, and demonstrate the therapeutic potential of inhibiting TNFα activity to rescue and restore adaptive spinal plasticity to the injured spinal cord. TNFα modulation represents a novel therapeutic target for improving rehabilitation after spinal cord injury.     

Structural Plasticity Can Produce Metaplasticity

Background

Synaptic plasticity underlies many aspect of learning memory and development. The properties of synaptic plasticity can change as a function of previous plasticity and previous activation of synapses, a phenomenon called metaplasticity. Synaptic plasticity not only changes the functional connectivity between neurons but in some cases produces a structural change in synaptic spines; a change thought to form a basis for this observed plasticity. Here we examine to what extent structural plasticity of spines can be a cause for metaplasticity. This study is motivated by the observation that structural changes in spines are likely to affect the calcium dynamics in spines. Since calcium dynamics determine the sign and magnitude of synaptic plasticity, it is likely that structural plasticity will alter the properties of synaptic plasticity.

Methodology/Principal Findings

In this study we address the question how spine geometry and alterations of N-methyl-D-aspartic acid (NMDA) receptors conductance may affect plasticity. Based on a simplified model of the spine in combination with a calcium-dependent plasticity rule, we demonstrated that after the induction phase of plasticity a shift of the long term potentiation (LTP) or long term depression (LTD) threshold takes place. This induces a refractory period for further LTP induction and promotes depotentiation as observed experimentally. That resembles the BCM metaplasticity rule but specific for the individual synapse. In the second phase, alteration of the NMDA response may bring the synapse to a state such that further synaptic weight alterations are feasible. We show that if the enhancement of the NMDA response is proportional to the area of the post synaptic density (PSD) the plasticity curves most likely return to the initial state.

Conclusions/Significance

Using simulations of calcium dynamics in synaptic spines, coupled with a biophysically motivated calcium-dependent plasticity rule, we find under what conditions structural plasticity can form the basis of synapse specific metaplasticity.     

Mechanisms of heterosynaptic metaplasticity

Synaptic plasticity is fundamental to the neural processes underlying learning and memory. Interestingly, synaptic plasticity itself can be dynamically regulated by prior activity, in a process termed ‘metaplasticity’, which can be expressed both homosynaptically and heterosynaptically. Here, we focus on heterosynaptic metaplasticity, particularly long-range interactions between synapses spread across dendritic compartments, and review evidence for intracellular versus intercellular signalling pathways leading to this effect. Of particular interest is our previously reported finding that priming stimulation in stratum oriens of area CA1 in the hippocampal slice heterosynaptically inhibits subsequent long-term potentiation and facilitates long-term depression in stratum radiatum. As we have excluded the most likely intracellular signalling pathways that might mediate this long-range heterosynaptic effect, we consider the hypothesis that intercellular communication may be critically involved. This hypothesis is supported by the finding that extracellular ATP hydrolysis, and activation of adenosine A2 receptors are required to induce the metaplastic state. Moreover, delivery of the priming stimulation in stratum oriens elicited astrocytic calcium responses in stratum radiatum. Both the astrocytic responses and the metaplasticity were blocked by gap junction inhibitors. Taken together, these findings support a novel intercellular communication system, possibly involving astrocytes, being required for this type of heterosynaptic metaplasticity.     

Metaplasticity gated through differential regulation of GluN2A versus GluN2B receptors by Src family kinases

Metaplasticity is a higher form of synaptic plasticity that is essential for learning and memory, but its molecular mechanisms remain poorly understood. Here, we report that metaplasticity of transmission at CA1 synapses in the hippocampus is mediated by Src family kinase regulation of NMDA receptors (NMDARs). We found that stimulation of G-protein-coupled receptors (GPCRs) regulated the absolute contribution of GluN2A-versus GluN2B-containing NMDARs in CA1 neurons: pituitary adenylate cyclase activating peptide 1 receptors (PAC1Rs) selectively recruited Src kinase, phosphorylated GluN2ARs, and enhanced their functional contribution; dopamine 1 receptors (D1Rs) selectively stimulated Fyn kinase, phosphorylated GluN2BRs, and enhanced these currents. Surprisingly, PAC1R lowered the threshold for long-term potentiation while long-term depression was enhanced by D1R. We conclude that metaplasticity is gated by the activity of GPCRs, which selectively target subtypes of NMDARs via Src kinases.     

NMDA receptor-dependent ocular dominance plasticity in adult visual cortex

The binocular region of mouse visual cortex is strongly dominated by inputs from the contralateral eye. Here we show in adult mice that depriving the dominant contralateral eye of vision leads to a persistent, NMDA receptor-dependent enhancement of the weak ipsilateral-eye inputs. These data provide in vivo evidence for metaplasticity as a mechanism for binocular competition and demonstrate that an ocular dominance shift can occur solely by the mechanisms of response enhancement. They also show that adult mouse visual cortex has a far greater potential for experience-dependent plasticity than previously appreciated. These insights may force a revision in how data on ocular dominance plasticity in mutant mice have been interpreted.     

Stable continual learning through structured multiscale plasticity manifolds

Biological plasticity is ubiquitous. How does the brain navigate this complex plasticity space, where any component can seemingly change, in adapting to an ever-changing environment? We build a systematic case that stable continuous learning is achieved by structured rules that enforce multiple, but not all, components to change together in specific directions. This rule-based low-dimensional plasticity manifold of permitted plasticity combinations emerges from cell type–specific molecular signaling and triggers cascading impacts that span multiple scales. These multiscale plasticity manifolds form the basis for behavioral learning and are dynamic entities that are altered by neuromodulation, metaplasticity, and pathology. We explore the strong links between heterogeneities, degeneracy, and plasticity manifolds and emphasize the need to incorporate plasticity manifolds into learning-theoretical frameworks and experimental designs.     

A Calcium-Dependent Plasticity Rule for HCN Channels Maintains Activity Homeostasis and Stable Synaptic Learning

Theoretical and computational frameworks for synaptic plasticity and learning have a long and cherished history, with few parallels within the well-established literature for plasticity of voltage-gated ion channels. In this study, we derive rules for plasticity in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and assess the synergy between synaptic and HCN channel plasticity in establishing stability during synaptic learning. To do this, we employ a conductance-based model for the hippocampal pyramidal neuron, and incorporate synaptic plasticity through the well-established Bienenstock-Cooper-Munro (BCM)-like rule for synaptic plasticity, wherein the direction and strength of the plasticity is dependent on the concentration of calcium influx. Under this framework, we derive a rule for HCN channel plasticity to establish homeostasis in synaptically-driven firing rate, and incorporate such plasticity into our model. In demonstrating that this rule for HCN channel plasticity helps maintain firing rate homeostasis after bidirectional synaptic plasticity, we observe a linear relationship between synaptic plasticity and HCN channel plasticity for maintaining firing rate homeostasis. Motivated by this linear relationship, we derive a calcium-dependent rule for HCN-channel plasticity, and demonstrate that firing rate homeostasis is maintained in the face of synaptic plasticity when moderate and high levels of cytosolic calcium influx induced depression and potentiation of the HCN-channel conductance, respectively. Additionally, we show that such synergy between synaptic and HCN-channel plasticity enhances the stability of synaptic learning through metaplasticity in the BCM-like synaptic plasticity profile. Finally, we demonstrate that the synergistic interaction between synaptic and HCN-channel plasticity preserves robustness of information transfer across the neuron under a rate-coding schema. Our results establish specific physiological roles for experimentally observed plasticity in HCN channels accompanying synaptic plasticity in hippocampal neurons, and uncover potential links between HCN-channel plasticity and calcium influx, dynamic gain control and stable synaptic learning.     

Sequential learning of pheromonal cues modulates memory consolidation in trainer-specific associative courtship conditioning

BACKGROUND: Associative memory formation requires that animals choose predictors for experiences they need to remember. When an artificial odor is paired with an aversive experience, that odor becomes the predictor. In more natural settings, however, animals can have multiple salient experiences that need to be remembered and prioritized. The mechanisms by which animals deal with multiple experiences are incompletely understood. RESULTS: Here we show that Drosophila males can be trained to discriminate between different types of female pheromones; they suppress courtship specifically to the type of female that was associated with unsuccessful courtship. Such "trainer-specific" learning is mediated by hydrocarbon olfactory cues and modifies the male's processing of those cues. Animals that are unable to use olfactory cues can still learn by using other sensory modalities, but memory in this case is not specific to the trainer female's maturation state. Concurrent and serial presentation of different pheromones demonstrates that the ability to consolidate memory of pheromonal cues can be modified by the temporal order in which they appear. CONCLUSION: Suppression of memory by new learning demonstrates that the dynamics of memory consolidation are subject to plasticity in Drosophila. This type of metaplasticity is essential for navigation of experience-rich natural environments.     

Calcium control of triphasic hippocampal STDP

Synaptic plasticity is believed to represent the neural correlate of mammalian learning and memory function. It has been demonstrated that changes in synaptic conductance can be induced by approximately synchronous pairings of pre- and post- synaptic action potentials delivered at low frequencies. It has also been established that NMDAr-dependent calcium influx into dendritic spines represents a critical signal for plasticity induction, and can account for this spike-timing dependent plasticity (STDP) as well as experimental data obtained using other stimulation protocols. However, subsequent empirical studies have delineated a more complex relationship between spike-timing, firing rate, stimulus duration and post-synaptic bursting in dictating changes in the conductance of hippocampal excitatory synapses. Here, we present a detailed biophysical model of single dendritic spines on a CA1 pyramidal neuron, describe the NMDAr-dependent calcium influx generated by different stimulation protocols, and construct a parsimonious model of calcium driven kinase and phosphatase dynamics that dictate the probability of stochastic transitions between binary synaptic weight states in a Markov model. We subsequently demonstrate that this approach can account for a range of empirical observations regarding the dynamics of synaptic plasticity induced by different stimulation protocols, under regimes of pharmacological blockade and metaplasticity. Finally, we highlight the strengths and weaknesses of this parsimonious, unified computational synaptic plasticity model, discuss differences between the properties of cortical and hippocampal plasticity highlighted by the experimental literature, and the manner in which further empirical and theoretical research might elucidate the cellular basis of mammalian learning and memory function.     

Stress,metaplasticity, and antidepressants

A large body of evidence has established a link between stressful life events and development or exacerbation of depression. At the cellular level, evidence has emerged indicating neuronal atrophy and cell loss in response to stress and in depression. At the molecular level, it has been suggested that these cellular deficiencies, mostly detected in the hippocampus, result from a decrease in the expression of brain-derived neurotrophic factor (BDNF) associated with elevation of glucocorticoids. Thus, an increase in expression of BDNF, facilitating both neuronal survival and neurogenesis, is thought to represent a converging mechanism of action of various types of antidepressant treatments (e.g., antidepressant drugs and transcranial magnetic stimulation). However, as also revealed by converging lines of evidence, high levels of glucocorticoids down-regulate hippocampal synaptic connectivity ('negative' metaplasticity), whereas an increase in expression of BDNF up-regulates connectivity in the hippocampus ('positive' metaplasticity). Therefore, antidepressant treatments might not only restore cell density but also regulate higher-order synaptic plasticity in the hippocampus by abolishing 'negative' metaplasticity, and thus restore hippocampal cognitive processes that are altered by stress and in depressed patients. This antidepressant regulatory effect on hippocampal synaptic plasticity function, which may, in turn, suppress 'negative' metaplasticity in other limbic structures, is discussed.     

Bidirectional synaptic plasticity: from theory to reality

Theories of receptive field plasticity and information storage make specific assumptions for how synapses are modified. I give a personal account of how testing the validity of these assumptions eventually led to a detailed understanding of long-term depression and metaplasticity in hippocampal area CA1 and the visual cortex. The knowledge of these molecular mechanisms now promises to reveal when and how sensory experience modifies synapses in the cerebral cortex.     

Invited review: Intermittent hypoxia and respiratory plasticity.

Intermittent hypoxia elicits long-term facilitation (LTF), a persistent augmentation (hours) of respiratory motor output. Considerable recent progress has been made toward an understanding of the mechanisms and manifestations of this potentially important model of respiratory plasticity. LTF is elicited by intermittent but not sustained hypoxia, indicating profound pattern sensitivity in its underlying mechanism. During intermittent hypoxia, episodic spinal serotonin receptor activation initiates cell signaling events, increasing spinal protein synthesis. One associated protein is brain-derived neurotrophic factor, a neurotrophin implicated in several forms of synaptic plasticity. Our working hypothesis is that increased brain-derived neurotrophic factor enhances glutamatergic synaptic currents in phrenic motoneurons, increasing their responsiveness to bulbospinal inspiratory inputs. LTF is heterogeneous among respiratory outputs, differs among experimental preparations, and is influenced by age, gender, and genetics. Furthermore, LTF is enhanced following chronic intermittent hypoxia, indicating a degree of metaplasticity. Although the physiological relevance of LTF remains unclear, it may reflect a general mechanism whereby intermittent serotonin receptor activation elicits respiratory plasticity, adapting system performance to the ever-changing requirements of life.     

Corequirement of PICK1 binding and PKC phosphorylation for stable surface expression of the metabotropic glutamate receptor mGluR7

The presynaptic metabotropic glutamate receptor (mGluR) mGluR7 modulates excitatory neurotransmission by regulating neurotransmitter release and plays a critical role in certain forms of synaptic plasticity. Although the dynamic regulation of mGluR7 surface expression governs a form of metaplasticity in the hippocampus, little is known about the molecular mechanisms regulating mGluR7 trafficking. We now show that mGluR7 surface expression is stabilized by both PKC phosphorylation and by receptor binding to the PDZ domain-containing protein PICK1. Phosphorylation of mGluR7 on serine 862 (S862) inhibits CaM binding, thereby increasing mGluR7 surface expression and receptor binding to PICK1. Furthermore, in mice lacking PICK1, PKC-dependent increases in mGluR7 phosphorylation and surface expression are diminished, and mGluR7-dependent plasticity at mossy fiber-interneuron hippocampal synapses is impaired. These data support a model in which PICK1 binding and PKC phosphorylation act together to stabilize mGluR7 on the cell surface in vivo.     

Converging evidence for a simplified biophysical model of synaptic plasticity

 Different mechanisms that could form the molecular basis for bi-directional synaptic plasticity have been identified experimentally and corresponding biophysical models can be constructed. However, such models are complex and therefore it is hard to deduce their consequences to compare them to existing abstract models of synaptic plasticity. In this paper we examine two such models: a phenomenological one inspired by the phenomena of AMPA receptor insertion, and a more complex biophysical model based on the phenomena of AMPA receptor phosphorylation. We show that under certain approximations both these models can be mapped on to an equivalent, calcium-dependent, differential equation. Intracellular calcium concentration varies locally in each postsynaptic compartment, thus the plasticity rule we extract is a single-synapse rule. We convert this single synapse plasticity equation to a multi-synapse rule by incorporating a model of the NMDA receptor. Finally we suggest a mathematical embodiment of metaplasticity, which is consistent with observations on NMDA receptor properties and dependence on cellular activity. These results, in combination with some of our previous results, produce converging evidence for the calcium control hypothesis including a dependence of synaptic plasticity on the level of intercellular calcium as well as on the temporal pattern of calcium transients. Received: 24 April 2002 / Accepted: 15 May 2002 Acknowledgements. LCY was supported by a Burroughs Wellcome fellowship, GCC by Murst 60%. Correspondence to: H. Z. Shouval (e-mail: Harel_Shouval@brown.edu)     

A molecular biological approach to synaptic plasticity and learning

Until the more recent advances made in molecular biology, attempts to link synaptic plasticity and learning have focused on using LTP as a marker of learning-induced synaptic plasticity, where one has expected to observe the same magnitude of change in synaptic strength as that observed with artificial stimulation. To a large extent this approach has been frustrated by the fact that it is generally assumed that the representation of the memory traces is distributed thoughout widespread networks of cells. By implication it is more likely that one would observe small distributed changes within a network; a formidable task to measure. In this review we describe how the advances in molecular biology give us both the tools to investigate the mechanisms of synaptic plasticity and to apply these to investigations of the underlying mechanisms in learning and the formation of memories that have until now remained out of our grasp.     

Neurotransmission: emerging roles of endocannabinoids

Postsynaptic release of endocannabinoids can inhibit presynaptic neurotransmitter release on short and long timescales. This retrograde inhibition occurs at both excitatory and inhibitory synapses and may provide a mechanism for synaptic gain control, short-term associative plasticity, reduction of synaptic crosstalk, and metaplasticity.     

Homeostatic plasticity in the CNS: synaptic and intrinsic forms

The study of experience-dependent plasticity has been dominated by questions of how Hebbian plasticity mechanisms act during learning and development. This is unsurprising as Hebbian plasticity constitutes the most fully developed and influential model of how information is stored in neural circuits and how neural circuitry can develop without extensive genetic instructions. Yet Hebbian plasticity may not be sufficient for understanding either learning or development: the dramatic changes in synapse number and strength that can be produced by this kind of plasticity tend to threaten the stability of neural circuits. Recent work has suggested that, in addition to Hebbian plasticity, homeostatic regulatory mechanisms are active in a variety of preparations. These mechanisms alter both the synaptic connections between neurons and the intrinsic electrical properties of individual neurons, in such a way as to maintain some constancy in neuronal properties despite the changes wrought by Hebbian mechanisms. Here we review the evidence for homeostatic plasticity in the central nervous system, with special emphasis on results from cortical preparations.