Calcium homeostasis and modulation of synaptic plasticity in the aged brain

The level of intracellular Ca2+ plays a central role in normal and pathological signaling within and between neurons. These processes involve a cascade of events for locally raising and lowering cytosolic Ca2+. As the mechanisms for age-related alteration in Ca2+ dysregulation have been illuminated, hypotheses concerning Ca2+ homeostasis and brain aging have been modified. The idea that senescence is due to pervasive cell loss associated with elevated resting Ca2+ has been replaced by concepts concerning changes in local Ca2+ levels associated with neural activity. This article reviews evidence for a shift in the sources of intracellular Ca2+ characterized by a diminished role for N-methyl-D-aspartate receptors and an increased role for intracellular stores and voltage-dependent Ca2+ channels. Physiological and biological models are outlined, which relate a shift in Ca2+ regulation with changes in cell excitability and synaptic plasticity, resulting in a functional lesion of the hippocampus.     

Complexities and uncertainties of neuronal network function

The nervous system generates behaviours through the activity in groups of neurons assembled into networks. Understanding these networks is thus essential to our understanding of nervous system function. Understanding a network requires information on its component cells, their interactions and their functional properties. Few networks come close to providing complete information on these aspects. However, even if complete information were available it would still only provide limited insight into network function. This is because the functional and structural properties of a network are not fixed but are plastic and can change over time. The number of interacting network components, their (variable) functional properties, and various plasticity mechanisms endows networks with considerable flexibility, but these features inevitably complicate network analyses. This review will initially discuss the general approaches and problems of network analyses. It will then examine the success of these analyses in a model spinal cord locomotor network in the lamprey, to determine to what extent in this relatively simple vertebrate system it is possible to claim detailed understanding of network function and plasticity.     

Calcium-transporting systems and calcium regulation in cardiomyocytes

The review systematizes and analyzes recent data about the role of different Ca(2+)-transport mechanisms in the regulation of Ca2+ metabolism and functional activity of the cardiomyocytes. During the cardiac action potential, Ca2+ enters the cardiomyocytes through sarcolemmal L-type calcium channels and via the Na+/Ca2+ exchange. This Ca2+ activates the release of additional Ca2+ from the sarcoplasmic reticulum. The sum of calcium from sarcolemmal influxes and sarcoplasmic release produces contractile effect. For the occurrence of relaxation, Ca2+ remove from the cytoplasm by three mechanisms, namely, sarcoplasmic Ca2+ pump, Na+/Ca2+ exchange and sarcolemmal Ca2+ pump. In this review, the structural and functional properties of the Ca2+ transport systems in the sarcolemmal membranes, sarcoplasmic reticulum and mitochondria are discussed. In addition alterations in regulation of intracellular calcium by activation of beta- and alpha-adrenergic receptors are consider.     

Synaptic information processing by astrocytes.

Glial cells were classically considered as supportive cells that do not contribute to information processing in the nervous system. However, considerable amount of evidence obtained by several groups during the last few years has demonstrated the existence of a bidirectional communication between astrocytes and neurons, which prompted a re-examination of the role of glial cells in the physiology of the nervous system. This review will discuss recent advances in the neuron-to-astrocyte communication, focusing on the recently reported properties of the synaptically evoked astrocyte Ca2+ signal that indicate that astrocytes show integrative properties for synaptic information processing. Indeed, we have recently shown that hippocampal astrocytes discriminate between the activity of different synapses, and respond selectively to different axon pathways. Furthermore, the astrocyte Ca2+ signal is modulated by the simultaneous activity of different synaptic inputs. This Ca2+ signal modulation depends on cellular intrinsic properties of the astrocytes, is bidirectionally regulated by the level of synaptic activity, and controls the spatial extension of the intracellular Ca2+ signal. Consequently, we propose that astrocytes can be considered as cellular elements involved in information processing by the nervous system.     

Neuronal calcium stores

Neuronal calcium stores associated with specialized intracellular organelles, such as endoplasmic reticulum and mitochondria, dynamically participate in generation of cytoplasmic calcium signals which accompany neuronal activity. They fulfil a dual role in neuronal Ca2+ homeostasis being involved in both buffering the excess of Ca2+ entering the cytoplasm through plasmalemmal channels and providing an intracellular source for Ca2+. Increase of Ca2+ content within the stores regulates the availability and magnitude of intracellular calcium release, thereby providing a mechanism which couples the neuronal activity with functional state of intracellular Ca2+ stores. Apart of 'classical' calcium stores (endoplasmic reticulum and mitochondria) other organelles (e.g. nuclear envelope and neurotransmitter vesicles) may potentially act as a functional Ca2+ storage compartments. Calcium ions released from internal stores participate in many neuronal functions, and might be primarily involved in regulation of various aspects of neuronal plasticity.     

Alternative roles for Cdk5 in learning and synaptic plasticity

Protein kinases mediate the intracellular signal transduction pathways controlling synaptic plasticity in the central nervous system. While the majority of protein kinases achieve this function via the phosphorylation of synaptic substrates, some kinases may contribute through alternative mechanisms in addition to enzymatic activity. There is growing evidence that protein kinases may often play structural roles in plasticity as well. Cyclin-dependent kinase 5 (Cdk5) has been implicated in learning and synaptic plasticity. Initial scrutiny focused on its enzymatic activity using pharmacological inhibitors and genetic modifications of Cdk5 cofactors. Quite recently Cdk5 has been shown to govern learning and plasticity via regulation of glutamate receptor degradation, a function that may not dependent on phosphorylation of downstream effectors. From these new studies, two roles emerge for Cdk5 in plasticity: one in which it controls structural plasticity via phosphorylation of synaptic substrates, and a second where it regulates functional plasticity via protein-protein interactions.     

Loss of Ryanodine Receptor 2 impairs neuronal activity-dependent remodeling of dendritic spines and triggers compensatory neuronal hyperexcitability

Dendritic spines are postsynaptic domains that shape structural and functional properties of neurons. Upon neuronal activity, Ca²⁺ transients trigger signaling cascades that determine the plastic remodeling of dendritic spines, which modulate learning and memory. Here, we study in mice the role of the intracellular Ca²⁺ channel Ryanodine Receptor 2 (RyR2) in synaptic plasticity and memory formation. We demonstrate that loss of RyR2 in pyramidal neurons of the hippocampus impairs maintenance and activity-evoked structural plasticity of dendritic spines during memory acquisition. Furthermore, post-developmental deletion of RyR2 causes loss of excitatory synapses, dendritic sparsification, overcompensatory excitability, network hyperactivity and disruption of spatially tuned place cells. Altogether, our data underpin RyR2 as a link between spine remodeling, circuitry dysfunction and memory acquisition, which closely resemble pathological mechanisms observed in neurodegenerative disorders.Subject terms: Neuroscience, Neurological disorders     

Ca2+ and synaptic plasticity

The induction and maintenance of synaptic plasticity is well established to be a Ca2+-dependent process. The use of fluorescent imaging to monitor changes [Ca2+]i in neurones has revealed a diverse array of signaling patterns across the different compartments of the cell. The Ca2+ signals within these compartments are generated by voltage or ligand-gated Ca2+ influx, and release from intracellular stores. The changes in [Ca2+]i are directly linked to the activity of the neurone, thus a neurone's input and output is translated into a dynamic Ca2+ code. Despite considerable progress in measuring this code much still remains to be determined in order to understand how the code is interpreted by the Ca2+ sensors that underlie the induction of compartment-specific plastic changes.     

Investigations of calcium homeostasis mechanisms in nerve cells and their alterations during brain pathology

The paper summarises new data about the molecular mechanisms of calcium homeostasis maintenance in nerve cells and generation of intracellular calcium transients--the most general secondary messenger triggering or modulating all steps of neuronal life cycle and its main functions. It describes the low- and high-voltage activated plasmalemmal ion channels injecting Ca2+ into the cell, cytosolic buffering systems which rapidly bind the main part of injected ions, properties of intracellular stores accumulating Ca2+ ions due to the activity of CERCA-pumps and releasing them back into the cytosol via the CICR mechanism, possible participation of mitochondria in this process, extrusion of Ca2+ from the cell by PMCA-pumps. By introducing new techniques, quantitative characteristics are obtained of these mechanisms and of their participation in determining the amplitude and kinetics of calcium signals in different neurons, as well as their changes during ageing and some forms of brain pathology.     

Intracellular Ca(2+) pools in neuronal signalling

Different intracellular pools participate in generating Ca(2+) signals in neuronal cells and in shaping their spatio-temporal patterns. They include the endoplasmic reticulum (endowed with different classes of Ca(2+) channels, with distinct functional properties and highly defined expression patterns in the brain), the Golgi apparatus, and the mitochondria. The release of Ca(2+) from intracellular pools plays an important role in controlling processes such as neurite outgrowth, synaptic plasticity, secretion and neurodegeneration.     

心肌细胞发育过程中胞浆内钙稳态的调控

Ca^2＋信号是细胞和各器官生长发育、行使其生理功能的基础,维持心肌细胞的钙稳态是保持正常心脏功能的先决条件。作为在胚胎发育过程中最早出现并行使功能的器官,胚胎期心脏的形态结构发生了明显的变化,泵血功能不断增强,以适应不断增强的机体的生理需求。从胚胎到成年,心肌细胞的功能有非常大的改变,各钙离子通道的表达也发生明显变化。因此,发育早期心肌细胞的钙稳态调控与成熟心肌细胞有明显的不同,在发育过程中引起细胞收缩的Ca^2＋来源也有明显的变化。随着分子和细胞生物学研究的发展,以及胚胎干细胞体外分化模型的应用,人们对心肌细胞发育过程中钙稳态的调控有了进一步的认识。本文综述了早期心肌细胞发育过程中胞浆内钙稳态的变化,总结了早期心肌细胞钙稳态调控机制的最新研究进展。     

Regulation of calcium signaling by the second messenger cyclic adenosine diphosphoribose (cADPR)

Ca2+ ions are involved in the regulation of many diverse functions in animal and plant cells, e.g. muscle contraction, secretion of neurotransmitters, hormones and enzymes, fertilization of oocytes, and lymphocyte activation and proliferation. The intracellular Ca2+ concentration can be increased by different molecular mechanisms, such as Ca2+ influx from the extracellular space or Ca2+ release from intracellular Ca2+ stores. Release from intracellular Ca2+ stores is accomplished by the small molecular compounds D-myo-inositol 1,4,5-trisphosphate (InsP3), cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP). This review will focus on the effects of cADPR in different cells and tissues, the mechanisms of cADPR-mediated Ca2+ release and Ca2+ entry, extracellular effects of cADPR, and the role of cADPR in a cell system studied in detail, human T-lymphocytes.     

Identification of a high-affinity Ca2+ pump associated with endocytotic vesicles in Dictyostelium discoideum

In the cellular slime mold Dictyostelium discoideum, changes in free cytosolic Ca2+ are thought to regulate certain processes during cell aggregation and differentiation. To understand the mechanisms controlling free Ca2+ levels in this organism, we previously isolated and characterized an ATP/Mg2+-dependent, high-affinity Ca2+ pump which appeared to be a component of "inside-out" plasma membrane vesicles [J. L. Milne and M. B. Coukell (1988) Biochem. J. 249. 223-230]. In this report, we demonstrate that a high-affinity Ca2+ pump, with properties virtually identical to the isolated pump, can be detected in filipin- or digitonin-permeabilized cells of Dictyostelium. Moreover, Ca2+-pumping vesicles, which migrate on Percoll/KCl gradients like the vesicles identified earlier, can be isolated from the permeabilized cells. Results of additional experiments suggest that this intracellular Ca2+ transporter is associated with a high-capacity non-IP3-releasable Ca2+ store which is generated by endocytosis. A possible role for this store in maintaining Ca2+ homeostasis in Dictyostelium is discussed.     

Calcium permeability of ligand-gated channels

Ligand-gated channels activated by excitatory neurotransmitters: glutamate, acetylcholine, ATP or serotonin are cation channels permeable to Ca2+. Molecular cloning revealed a large variety of the ligand-gated channel subunits differentially expressed in mammalian brain. Many of them have different Ca2+ permeability providing immense diversity in Ca2+ entry mediated by ligand-gated channels during synaptic transmission. Functional analysis of cloned channels allowed to identify structural elements in the pore forming regions determining Ca2+ permeability for many types of ligand-gated channels. The functional role of the Ca2+ entry mediated by various ligand-gated channels in mammalian central nervous system is less understood. The studies reviewed in this article provide information about known structural determinants of Ca2+ permeability of the ligand-gated channels and the role of this particular pathway of Ca2+ entry in cell function.     

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).     

Extracellular calcium acts as a "third messenger" to regulate enzyme and alkaline secretion

It is generally assumed that the functional consequences of stimulation with Ca2+ -mobilizing agonists are derived exclusively from the second messenger action of intracellular Ca2+, acting on targets inside the cells. However, during Ca2+ signaling events, Ca2+ moves in and out of the cell, causing changes not only in intracellular Ca2+, but also in local extracellular Ca2+. The fact that numerous cell types possess an extracellular Ca2+ "sensor" raises the question of whether these dynamic changes in external [Ca2+] may serve some sort of messenger function. We found that in intact gastric mucosa, the changes in extracellular [Ca2+] secondary to carbachol-induced increases in intracellular [Ca2+] were sufficient and necessary to elicit alkaline secretion and pepsinogen secretion, independent of intracellular [Ca2+] changes. These findings suggest that extracellular Ca2+ can act as a "third messenger" via Ca2+ sensor(s) to regulate specific subsets of tissue function previously assumed to be under the direct control of intracellular Ca2+.     

Synaptic activity augments muscarinic acetylcholine receptor-stimulated inositol 1,4,5-trisphosphate production to facilitate Ca2+ release in hippocampal neurons

Intracellular Ca2+ store release contributes to activity-dependent synaptic plasticity in the central nervous system by modulating the amplitude, propagation, and temporal dynamics of cytoplasmic Ca2+ changes. However, neuronal Ca2+ stores can be relatively insensitive to increases in the store-mobilizing messenger inositol 1,4,5-trisphosphate (IP3). Using a fluorescent biosensor we have visualized M1 muscarinic acetylcholine (mACh) receptor signaling in individual hippocampal neurons and observed increased IP3 production in the absence of concurrent Ca2+ store release. However, coincident glutamate-mediated synaptic activity elicited enhanced and oscillatory IP3 production that was dependent upon ongoing mACh receptor stimulation and S-alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid receptor activation of Ca2+ entry. Moreover, the enhanced levels of IP3 now mobilized Ca2+ from intracellular stores that were refractory to the activation of mACh receptors alone. We conclude that convergent ionotropic and metabotropic receptor inputs can facilitate Ca2+ signaling by enhancing IP3 production as well as augmenting release by Ca2+-induced Ca2+ release.     

Regulation of AMPA Receptors by Phosphorylation

The AMPA receptors for glutamate are oligomeric structures that mediate fast excitatory responses in the central nervous system. Phosphorylation of AMPA receptors is an important mechanism for short-term modulation of their function, and is thought to play an important role in synaptic plasticity in different brain regions. Recent studies have shown that phosphorylation of AMPA receptors by cAMP-dependent protein kinase (PKA) and Ca2+- and calmodulin-dependent protein kinase II (CaMKII) potentiates their activity, but phosphorylation of the receptor subunits may also affect their interaction with intracellular proteins, and their expression at the plasma membrane. Phosphorylation of AMPA receptor subunits has also been investigated in relation to processes of synaptic plasticity. This review focuses on recent advances in understanding the molecular mechanisms of regulation of AMPA receptors, and their implications in synaptic plasticity.