The role of synaptic ion channels in synaptic plasticity

The nervous system receives a large amount of information about the environment through elaborate sensory routes. Processing and integration of these wide-ranging inputs often results in long-term behavioural alterations as a result of past experiences. These relatively permanent changes in behaviour are manifestations of the capacity of the nervous system for learning and memory. At the cellular level, synaptic plasticity is one of the mechanisms underlying this process. Repeated neural activity generates physiological changes in the nervous system that ultimately modulate neuronal communication through synaptic transmission. Recent studies implicate both presynaptic and postsynaptic ion channels in the process of synapse strength modulation. Here, we review the role of synaptic ion channels in learning and memory, and discuss the implications and significance of these findings towards deciphering the molecular biology of learning and memory.     

Eph-ephrin与突触可塑性

Eph受体酪氨酸激酶及其配体ephrin广泛参与神经系统的发育,如轴突导向、细胞迁移、体节形成和血管生成。最近研究显示的Ephephrin在突触的定位提示其与突触可塑性有关。Ephephrin对成年神经系统的可塑性、学习和记忆,以及神经损伤后的再生可能具有重要的调节作用。     

The role of different conformational states of receptors in the formation of synaptic plasticity

A mathematical model was proposed that explains the formation of successive temporal stages of synaptic plasticity in terms of the transition of post-synaptic ionotropic receptors to different conformational states.     

The physiological role of kainate receptors in the amygdala

The kainate subtype of glutamate receptors has received considerable attention in recent years, and a wealth of knowledge has been obtained regarding the function of these receptors. Kainate receptors have been shown to mediate synaptic transmission in some brain regions, modulate presynaptic release of glutamate and gamma-aminobutyric acid (GABA), and mediate synaptic plasticity or the development of seizure activity. This article focuses on the function of kainate receptors in the amygdala, a brain region that plays a central role in emotional behavior and certain psychiatric illnesses. Evidence is reviewed indicating that postsynaptic kainate receptors containing the glutamate receptor 5 kainate receptor (GLUk5) subunit are present on interneurons and pyramidal cells in the basolateral amygdala and mediate a component of the synaptic responses of these neurons to glutamatergic input. In addition, GLUk5-containing kainate receptors are present on presynaptic terminals of GABAergic neurons, where they modulate the release of GABA in an agonist concentration-dependent, bidirectional manner. GLUk5-containing kainate receptors also mediate a longlasting synaptic facilitation induced by low-frequency stimulation in the external capsule to the basolateral nucleus pathway, and they appear to be partly responsible for the susceptibility of the amygdala to epileptogenesis. Taken together, these findings have suggested a prominent role of GLUk5-containing kainate receptors in the regulation of neuronal excitability in the amygdala.     

代谢型谷氨酸受体在突触可塑性中的作用研究进展

突触可塑性是近 30年来神经科学领域的研究热点之一 ,它主要包括长时程增强 (long termpotentiation ,LTP)和长时程抑制 (long termdepression ,LTD)。以往的研究已经证实 ,离子型谷氨酸受体 (iGluRs)中的NMDA受体和AMPA受体 ,在LTP和LTD的诱导和维持中通过阳离子内流 ,引起细胞内的级联反应而起作用。新近的研究发现 ,代谢型谷氨酸受体 (mGluRs)与G蛋白偶联 ,通过细胞内的多种信使系统介导慢突触传递。本文主要就mGluRs在不同脑区LTP和LTD中的作用进行综述     

Reelin, lipoprotein receptors and synaptic plasticity

Apolipoprotein E (APOE) is a cholesterol transport protein and an isoform-specific major risk factor for neurodegenerative diseases. The lipoprotein receptors that bind APOE have recently been recognized as pivotal components of the neuronal signalling machinery. The interaction between APOE receptors and one of their ligands, reelin, allows them to function directly as signal transduction receptors at the plasma membrane to control not only neuronal positioning during brain development, but also synaptic plasticity in the adult brain. Here, we review the molecular mechanisms through which APOE, cholesterol, reelin and APOE receptors control synaptic functions that are essential for cognition, learning, memory, behaviour and neuronal survival.     

The role of cluster receptor state in synaptic plasticity

Common postsynaptic mechanisms underlying formation and increase in efficiency of glutamate and GABA synapses are discussed. Much attention is given to clusterization of different receptor types as a mechanism of long-term potentiation. A possibility of synchronization of activities of receptors forming the same cluster is discussed.     

The role of myosin V in exocytosis and synaptic plasticity

In neuroscience, myosin V motor proteins have attracted attention since they are highly expressed in brain, and absence of myosin Va in man leads to a severe neurological disease called Griscelli syndrome. While in some cells myosin V is described to act as a vesicle transport motor, an additional role in exocytosis has emerged recently. In neurons, myosin V has been linked to exocytosis of secretory vesicles and recycling endosomes. Through these functions, it is implied in regulating important brain functions including the release of neuropeptides by exocytosis of large dense-core vesicles and the insertion of neurotransmitter receptors into post-synaptic membranes. This review focuses on the role of myosin V in (i) axonal transport and stimulated exocytosis of large dense-core vesicles to regulate the secretion of neuroactive substances, (ii) tethering of the endoplasmic reticulum at cerebellar synapses to permit long-term depression, (iii) recycling of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors at hippocampal synapses during long-term potentiation, and (iv) recycling of nicotinic acetylcholine receptors at the neuromuscular junction. Myosin V is thus discussed as an important modulator of synaptic plasticity.     

代谢型谷氨酸受体在突触可塑性中的作用

突触可塑性是近几年神经科学研究的热点之一,因为它对于理解神经系统的学习、学习和记忆、多咱神经疾病等许多过程有着重要的意义。除了离子型谷氨酸受体外,代谢型谷氨酸受体也参与了一些脑区中不同形式的突触可塑性变化。本文就代谢型谷氨酸受体选择性激动剂和拮抗剂对长时程增强和长时程抑制的作用进行了综述,以助于人们进一步理解突触可塑性的细胞和分子机制。     

Regulatory mechanisms of AMPA receptors in synaptic plasticity

Activity-dependent changes in the strength of excitatory synapses are a cellular mechanism for the plasticity of neuronal networks that is widely recognized to underlie cognitive functions such as learning and memory. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors (AMPARs) are the main transducers of rapid excitatory transmission in the mammalian CNS, and recent discoveries indicate that the mechanisms which regulate AMPARs are more complex than previously thought. This review focuses on recent evidence that alterations to AMPAR functional properties are coupled to their trafficking, cytoskeletal dynamics and local protein synthesis. These relationships offer new insights into the regulation of AMPARs and synaptic strength by cellular signalling.     

Kainate receptors and RNA editing in cholinergic neurons

Parasympathetic ganglia are considered simple relay systems that have cholinergic input and output, with modulation occurring centrally. Greater complexity is suggested, however, by our showing here that avian ciliary ganglion (CG) neurons also express a different excitatory receptor type--ionotropic glutamate receptors of the kainate subtype (KARs). This is the first report of glutamate receptor expression in the CG and KAR expression in any cholinergic neuron. We show that KARs form functional channels on CG neurons. KARs localize to CG neuron axons and somata as well as axons and terminals of pre-synaptic inputs to the CG. Glutamate transporters are expressed on Schwann cells that surround synapses on neuronal somata, and may provide a local source of glutamate. CG neurons express multiple KAR subunit mRNAs (GluR5, GluR7, and KA1), and their relative levels change dramatically during axon outgrowth and synaptic differentiation. The developmental role for KARs may depend upon their calcium permeability, a property regulated by mRNA editing. We show GluR5 editing increases predominantly at the time CG axons contact peripheral targets. Our data suggest that glutamatergic signaling may function as a local circuit mechanism to modulate excitability and calcium signaling during synapse formation and maturation in the CG in vivo.     

The emerging role of RNA and DNA editing in cancer

Nucleotide sequence modification through single base editing in animals is emerging as an important player in tumorigenesis. RNA editing especially has increased greatly during mammalian evolution and modulates diverse cellular functions presumably in a context-dependent manner. Sequence editing impacts development, including pluripotency and hematopoiesis, and multiple recent studies have shown that dysregulation of editing is associated with tumor biology. Much is yet to be learned about the role of sequence editing in human biology but this process is a critical modulator of cell regulation and may present an attractive option for therapeutic intervention in cancer in the future.SignificanceSequence editing provides an additional regulatory layer of cancer initiation and progression that may be amenable to therapeutic design. Although editing of both RNA and DNA substrates has been known to occur for some time, the extent and implications of these modifications have been grossly underappreciated until recent genome-wide and disease-association studies were reported. This review highlights the cellular processes controlled by sequence editing, their implications in normal and cancerous states and considers potential targeted therapeutic strategies.     

The role of RNA editing by ADARs in RNAi

Adenosine deaminases that act on RNA (ADARs) are RNA-editing enzymes that deaminate adenosines to create inosines in double-stranded RNA (dsRNA). Here we demonstrate that ADARs are not required for RNA interference (RNAi) and that they do not antagonize the pathway to a detectable level when RNAi is initiated by injecting dsRNA. We find, however, that transgenes expressed in the somatic tissues of wild-type animals are silenced in strains with deletions in the two genes encoding ADARs, adr-1 and adr-2. Transgene-induced gene silencing in adr-1;adr-2 mutants depends on genes required for RNAi, suggesting that a dsRNA intermediate is involved. In wild-type animals we detect edited dsRNA corresponding to transgenes, and we propose that editing of this dsRNA prevents somatic transgenes from initiating RNAi in wild-type animals.     

The role of ECM molecules in activity-dependent synaptic development and plasticity

Growth and guidance of neurites (axons and dendrites) during development is the prerequisite for the establishment of functional neural networks in the adult organism. In the adult, mechanisms similar to those used during development may regulate plastic changes that underlie important nervous system functions, such as memory and learning. There is now ever-increasing evidence that extracellular matrix (ECM)-associated factors are critically involved in the formation of neuronal connections during development, and their plastic changes in the adult. Here, we review the current literature on the role of ECM components in activity-dependent synaptic development and plasticity, with the major focus on the thrombospondin type I repeat (TSR) domain-containing proteins. We propose that ECM components may modulate neuronal development and plasticity by: 1) regulating cellular motility and morphology, thus contributing to structural alterations that are associated with the expression of synaptic plasticity, 2) coordinating transsynaptic signaling during plasticity via their cell surface receptors, and 3) defining the physical parameters of the extracellular space, thereby regulating diffusion of soluble signaling molecules in the extracellular space (ECS).     

Leptin and its role in hippocampal synaptic plasticity

It is well documented that the hormone leptin plays a pivotal role in regulating food intake and body weight via its hypothalamic actions. However, leptin receptors are expressed throughout the brain with high levels found in the hippocampus. Evidence is accumulating that leptin has widespread actions on CNS function and in particular learning and memory. Recent studies have demonstrated that leptin-deficient or-insensitive rodents have impairments in hippocampal synaptic plasticity and in spatial memory tasks performed in the Morris water maze. Moreover, direct administration of leptin into the brain facilitates hippocampal long-term potentiation (LTP), and improves memory performance in mice. There is also evidence that, at the cellular level, leptin has the capacity to convert hippocampal short-term potentiation (STP) into LTP, via enhancing NMDA receptor function. Recent data indicates that leptin can also induce a novel form of NMDA receptor-dependent hippocampal long-term depression. Here, we review the evidence implicating a key role for the hormone leptin in modulating hippocampal synaptic plasticity and discuss the role of lipid signaling cascades in this process.     

MPTP modulates hippocampal synaptic transmission and activity-dependent synaptic plasticity via dopamine receptors

Parkinson's disease (PD)-like symptoms and cognitive deficits are inducible by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Since cognitive abilities, including memory formations rely also on hippocampus, we set out to clarify the effects of MPTP on hippocampal physiology. We show that bath-application of MPTP (25?μM) to acute hippocampal slices enhanced AMPA receptor-mediated field excitatory postsynaptic potentials (AMPAr-fEPSPs) transiently, whereas N-methyl-D-aspartate (NMDA) receptor-mediated fEPSPs (NMDAr-fEPSPs) were facilitated persistently. The MPTP-mediated transient AMPAr-fEPSP facilitation was antagonized by the dopamine D2-like receptor antagonists, eticlopride (1?μM) and sulpiride (1 and 40?μM). In contrast, the persistent enhancement of NMDAr-fEPSPs was prevented by the dopamine D1-like receptor antagonist SCH23390 (10?μM). In addition, we show that MPTP decreased paired-pulse facilitation of fEPSPs and mEPSCs frequency. Regarding activity-dependent synaptic plasticity, 25?μM MPTP transformed short-term potentiation (STP) into a long-term potentiation (LTP) and caused a slow onset potentiation of a non-tetanized synaptic input after induction of LTP in a second synaptic input. This heterosynaptic slow onset potentiation required activation of dopamine D1-like and NMDA-receptors. We conclude that acute MPTP application affects basal synaptic transmission by modulation of presynaptic vesicle release and facilitates NMDAr-fEPSPs as well as activity-dependent homo- and heterosynaptic plasticity under participation of dopamine receptors.     

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.