Brain Research Reviews最新文献

The proposal on the existence of two main modes of intercellular communication in the central nervous system (CNS) was introduced in 1986 and called wiring transmission (WT) and volume transmission (VT). The major criterion for this classification was the different characteristics of the communication channel with physical boundaries well delimited in the case of WT (axons and their synapses; gap junctions) but not in the case of VT (the extracellular fluid filled tortuous channels of the extracellular space and the cerebrospinal fluid filled ventricular space and sub-arachnoidal space). The basic dichotomic classification of intercellular communication in the brain is still considered valid, but recent evidence on the existence of unsuspected specialized structures for intercellular communication, such as microvesicles (exosomes and shedding vesicles) and tunnelling nanotubes, calls for a refinement of the original classification model. The proposed updating is based on criteria which are deduced not only from these new findings but also from concepts offered by informatics to classify the communication networks in the CNS. These criteria allowed the identification also of new sub-classes of WT and VT, namely the “tunnelling nanotube type of WT” and the “Roamer type of VT.” In this novel type of VT microvesicles are safe vesicular carriers for targeted intercellular communication of proteins, mtDNA and RNA in the CNS flowing in the extracellular fluid along energy gradients to reach target cells. In the tunnelling nanotubes proteins, mtDNA and RNA can migrate as well as entire organelles such as mitochondria. Although the existence and the role of these new types of intercellular communication in the CNS are still a matter of investigation and remain to be fully demonstrated, the potential importance of these novel types of WT and VT for brain function in health and disease is discussed.

In this article, we present a new view on the nature of cognitive processes suggesting that there is a common core, viz., automatic sensory–cognitive processes that form the basis for higher-order cognitive processes. It has been shown that automatic sensory–cognitive processes are shared by humans and various other species and occur at different developmental stages and even in different states of consciousness. This evidence, based on the automatic electrophysiological change-detection response mismatch negativity (MMN), its magnetoencephalographic equivalent MMNm, and behavioral data, indicates that in audition surprisingly complex processes occur automatically and mainly in the sensory-specific cortical regions. These processes include, e.g. stimulus anticipation and extrapolation, sequential stimulus–rule extraction, and pattern and pitch-interval encoding. Furthermore, these complex perceptual–cognitive processes, first found in waking adults, occur similarly even in sleeping newborns, anesthetized animals, and deeply sedated adult humans, suggesting that they form the common perceptual–cognitive core of cognitive processes in general. Although the present evidence originates mainly from the auditory modality, it is likely that analogous evidence could be obtained from other sensory modalities when measures corresponding to those used in the study of the auditory modality become available.

Synaptogenesis is a decisive process for the development of the brain, its plasticity during adulthood and its regeneration after injury and disease. Despite tremendous progress during the last decades, it remains unclear, whether neurons can form synapses autonomously. In this review, I will summarize recent evidence that this is probably not the case and that distinct phases of synapse development depend on help from glial cells. The results supporting this view come from studies on the central and peripheral nervous system and on different experimental models including cultured cells as well as living flies, worms and mice. Our understanding of synapse–glia interactions in the developing, adult and diseased brain is likely to advance more rapidly as new experimental approaches to identify, visualize and manipulate glial cells in vivo become available.

This review gives an overview of connexin expression in glial cells of the central nervous system, the different modes of connexin action, including gap junctional channels and hemichannels, as well as the available methodologies to measure their activity. We summarize the strengths and limitations of current pharmacological and genetic approaches to interfere with connexin channel functions. We outline new avenues not only to study specific mechanisms by which connexins exert these functions but also to selectively investigate well-defined coupling compartments among glial networks.

A growing body of evidence indicates that extracellular nucleotides play important roles in the regulation of neuronal and glial functions in the nervous system through P2 purinoceptors. P2 purinoceptors are divided into two families, ionotropic receptors (P2X) and metabotropic receptors (P2Y). P2X receptors (seven types; P2X1–P2X7) contain intrinsic pores that open by binding with ATP, and P2Y receptors (eight types; P2Y1, 2, 4, 6, 11, 12, 13 and 14) are activated by nucleotides and couple to intracellular second-messenger systems through heterotrimeric G-proteins. Nucleotides are released or leaked from non-excitable cells as well as neurons in physiological and pathophysiological conditions. Studies have shown that microglia, a type of glial cells known as resident macrophages in the CNS, express several subtypes of P2X and P2Y receptors, and these receptors play a key role in pain signaling in the spinal cord under pathological conditions such as by peripheral nerve injury (called neuropathic pain). Within the spinal dorsal horn, peripheral nerve injury leads to a progressive series of changes in microglia including morphological hypertrophy of the cell body and proliferation, which are considered indicative of activation. These activated microglia upregulate expression of P2X/Y receptors (e.g., P2X4 and P2Y12). Importantly, pharmacological, molecular and genetic manipulations of the function or expression of these microglial molecules strongly suppress neuropathic pain. We expect that further investigation to determine how ATP signaling via P2X receptors participates in the pathogenesis of chronic pain will lead to a better understanding of the molecular mechanisms of pathological pain and provide clues for the development of new therapeutic drugs.

Gliotransmitters are chemicals released from glial cells fulfilling a following set of criteria: (i) they are synthesized by and/or stored in glia; (ii) their regulated release is triggered by physiological and/or pathological stimuli; (iii) they activate rapid (milliseconds to seconds) responses in neighboring cells; and (iv) they play a role in (patho)physiological processes. Astrocytes can release a variety of gliotransmitters into the extracellular space using several different mechanisms. In this review, we focus on exocytotic mechanism(s) underlying the release of three classes of gliotransmitters: (i) amino acids, such as, glutamate and d-serine; (ii) nucleotides, like adenosine 5′-triphosphate; and (iii) peptides, such as, atrial natriuretic peptide and brain-derived neurotrophic factor. It is becoming clear that astrocytes are endowed with elements that qualify them as cells communicating with neurons and other cells within the central nervous system by employing regulated exocytosis.

The major glial population of the brain is constituted by astroglia. Highly branched and ramified protoplasmic astrocytes are the predominant form in grey matter and are found in almost all regions of the central nervous system. In cerebellum and retina, there two forms of elongated radial glia exist (Bergmann glia and Müller cells, respectively) that share many features with the protoplasmic astrocytes in respect to their perisynaptic association. Although these three astroglial cell types are different in their gross morphology, they are characterized by a polarized orientation of their processes. While one or only few processes have contacts with CNS boundaries such as capillaries and pia, an overwhelming number of thin filopodia- and lamellipodia-like process terminals contact and enwrap synapses, the sites of neuronal communication. The perisynaptic glial processes are the primary compartments that sense neuronal activity. After signal integration, they can also modulate synaptic transmission, thereby contributing to neural plasticity. Despite their importance, the mechanisms that (1) target astroglial processes toward pre- and postsynaptic compartments and (2) control the interaction during plastic events of the brain such as learning or injury are poorly understood. This review will summarize our current knowledge and highlight some open questions.

The maintenance of ion gradients across plasma membranes is a prerequisite for the establishment of cellular membrane potentials, electrical signalling, and metabolite transport. At active synapses, pre- and postsynaptic ion gradients are constantly challenged and used for signalling purposes. Perisynaptic glia, mainly represented by fine processes of astrocytes which get into close vicinity to neuronal synapses, are required to normalize the extracellular ionic milieu and maintain ion gradients. On the other hand, perisynaptic glia itself is activated by synaptically released transmitters binding to plasma membrane receptors and transmitter carriers, and experiences significant ion changes as well. In this review we present an overview of dynamic changes of the major ion species in astrocytes in response to neuronal, especially synaptic, activity. We will focus on calcium, sodium, and proton/hydroxyl ions that play key roles in signalling processes, and will discuss the functional consequences of the glial ion signals and homeostatic processes for synaptic transmission.

The concept of the tripartite synapse proposes that in addition to the presynapse and the postsynaptic membrane closely apposed processes of astrocytes constitute an integral part of the synapse. Accordingly, astrocytes may influence synaptic activity by various ways. Thus glia- and neuron-derived neurotrophins, cytokines and metabolites influence neuronal survival, synaptic activity and plasticity. Beyond these facts, the past years have shown that astrocytes are required for synaptogenesis, the structural maintenance and proper functioning of synapses. In particular, astrocytes seem to play a key role in the organization of the brain's extracellular matrix (ECM) — most prominently the so-called perineuronal nets (PNNs), complex macromolecular assemblies of ECM components. Due to progress in cellular and molecular neurosciences, it has been possible to decipher the composition of ECM structures and to obtain insight into their function(s) and underlying mechanisms. It appears that PNN-related structures are involved in regulating the sprouting and pruning of synapses, which represents an important morphological correlate of synaptic plasticity in the adult nervous system. Perturbation assays and gene elimination by recombinant techniques have provided clear indications that astrocyte-derived ECM components, e.g. the tenascins and chondroitinsulfate proteoglycans (CSPGs) of the lectican family participate in these biological functions. The present review will discuss the glia-derived glycoproteins and CSPGs of the perisynaptic ECM, their neuronal and glial receptors, and in vitro assays to test their physiological functions in the framework of the synapse, the pivotal element of communication in the central nervous system.