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.     

Morphological plasticity of rodent astroglia

In the past two decades, there has been an explosion of research on the role of neuroglial interactions in the control of brain homeostasis in both physiological and pathological conditions. Astrocytes, a subtype of glia in the central nervous system, are dynamic signaling elements that regulate neurogenesis and development of brain circuits, displaying intimate dynamic relationships with neurons, especially at synaptic sites where they functionally integrate the tripartite synapse. When astrocytes are isolated from the brain and maintained in culture, they exhibit a polygonal shape unlike their precursors in vivo. However, cultured astrocytes can be induced to undergo morphological plasticity leading to process formation, either by interaction with neurons or by the influence of pharmacological agents. This review highlights studies on the molecular mechanisms underlying morphological plasticity in astrocyte cultures and intact brain tissue, both in situ and in vivo.     

LAR-RPTPs: synaptic adhesion molecules that shape synapse development

The synapse is the most elementary operating unit in neurons, creating neural circuits that underlie all brain functions. Synaptic adhesion molecules initiate neuronal synapse connections, promote their stabilization and refinement, and control long-term synaptic plasticity. Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) have previously been implicated as essential elements in central nervous system (CNS) development. Recent studies have demonstrated that LAR-RPTP family members are also involved in diverse synaptic functions, playing a role in synaptic adhesion pathways together with a host of distinct transmembrane proteins and serving as major synaptic adhesion molecules in governing pre- and postsynaptic development, dysfunctions of which may underlie various disorders. This review highlights the emerging role of LAR-RPTPs as synapse organizers in orchestrating synapse development.     

Cortical maps: a role for astrocytes?

Astrocytes are a multifunctional cell type in the nervous system that can influence neurons and synapses in numerous ways. Astrocytes have been suggested to play important roles in synapse formation during development, as well as in multiple forms of synaptic plasticity in the developing and adult brain. Astrocytes respond to nearby neural activity with elevations in cytosolic calcium concentration, and in sensory cortex these calcium responses have been shown to be topographically aligned to neuronal sensory maps. Here, we review recent evidence for astrocyte interactions with neural circuits, with particular emphasis on how these interactions may shape the development, arrangement and plasticity of cortical sensory maps.     

Glial cells in (patho)physiology

Neuroglial cells define brain homeostasis and mount defense against pathological insults. Astroglia regulate neurogenesis and development of brain circuits. In the adult brain, astrocytes enter into intimate dynamic relationship with neurons, especially at synaptic sites where they functionally form the tripartite synapse. At these sites, astrocytes regulate ion and neurotransmitter homeostasis, metabolically support neurons and monitor synaptic activity; one of the readouts of the latter manifests in astrocytic intracellular Ca(2+) signals. This form of astrocytic excitability can lead to release of chemical transmitters via Ca(2+) -dependent exocytosis. Once in the extracellular space, gliotransmitters can modulate synaptic plasticity and cause changes in behavior. Besides these physiological tasks, astrocytes are fundamental for progression and outcome of neurological diseases. In Alzheimer's disease, for example, astrocytes may contribute to the etiology of this disorder. Highly lethal glial-derived tumors use signaling trickery to coerce normal brain cells to assist tumor invasiveness. This review not only sheds new light on the brain operation in health and disease, but also points to many unknowns.     

CNF1 improves astrocytic ability to support neuronal growth and differentiation in vitro

Modulation of cerebral Rho GTPases activity in mice brain by intracerebral administration of Cytotoxic Necrotizing Factor 1 (CNF1) leads to enhanced neurotransmission and synaptic plasticity and improves learning and memory. To gain more insight into the interactions between CNF1 and neuronal cells, we used primary neuronal and astrocytic cultures from rat embryonic brain to study CNF1 effects on neuronal differentiation, focusing on dendritic tree growth and synapse formation, which are strictly modulated by Rho GTPases. CNF1 profoundly remodeled the cytoskeleton of hippocampal and cortical neurons, which showed philopodia-like, actin-positive projections, thickened and poorly branched dendrites, and a decrease in synapse number. CNF1 removal, however, restored dendritic tree development and synapse formation, suggesting that the toxin can reversibly block neuronal differentiation. On differentiated neurons, CNF1 had a similar effacing effect on synapses. Therefore, a direct interaction with CNF1 is apparently deleterious for neurons. Since astrocytes play a pivotal role in neuronal differentiation and synaptic regulation, we wondered if the beneficial in vivo effect could be mediated by astrocytes. Primary astrocytes from embryonic cortex were treated with CNF1 for 48 hours and used as a substrate for growing hippocampal neurons. Such neurons showed an increased development of neurites, in respect to age-matched controls, with a wider dendritic tree and a richer content in synapses. In CNF1-exposed astrocytes, the production of interleukin 1β, known to reduce dendrite development and complexity in neuronal cultures, was decreased. These results demonstrate that astrocytes, under the influence of CNF1, increase their supporting activity on neuronal growth and differentiation, possibly related to the diminished levels of interleukin 1β. These observations suggest that the enhanced synaptic plasticity and improved learning and memory described in CNF1-injected mice are probably mediated by astrocytes.     

A trace of silence: memory and microRNA at the synapse

Identifying the neural circuits that mediate particular behaviors and uncovering their plasticity is an endeavor at the heart of neuroscience. This effort is allied with the elucidation of plasticity mechanisms, because the molecular determinants of plasticity can be markers for the neurons and synapses that are modified by experience. Of particular interest is protein synthesis localized to the synapse, which might establish and maintain the stable modification of neuronal properties, including the pattern and strength of synaptic connections. Recent studies reveal that microRNAs and the RISC pathway regulate synaptic protein synthesis. Is synaptic activity of the RISC pathway a molecular signature of memory?     

Experience-dependent plasticity in adult visual cortex

Experience-dependent plasticity is a prominent feature of the mammalian visual cortex. Although such neural changes are most evident during development, adult cortical circuits can be modified by a variety of manipulations, such as perceptual learning and visual deprivation. Elucidating the underlying mechanisms at the cellular and synaptic levels is an essential step in understanding neural plasticity in the mature animal. Although developmental and adult plasticity share many common features, notable differences may be attributed to developmental cortical changes at multiple levels. These range from shifts in the molecular profiles of cortical neurons to changes in the spatiotemporal dynamics of network activity. In this review, we will discuss recent progress and remaining challenges in understanding adult visual plasticity, focusing on the primary visual cortex.     

Astrocyte-synapse interactions during brain development

Bidirectional communication between astrocytes and neurons is essential for proper brain development. Astrocytes, a major glial cell type, are morphologically complex cells that directly interact with neuronal synapses to regulate synapse formation, maturation, and function. Astrocyte-secreted factors bind neuronal receptors to induce synaptogenesis with regional and circuit-level precision. Cell adhesion molecules mediate the direct contact between astrocytes and neurons, which is required for both synaptogenesis and astrocyte morphogenesis. Neuron-derived signals also shape astrocyte development, function, and molecular identity. This review highlights recent findings on the topic of astrocyte-synapse interactions, and discusses the importance of these interactions for synapse and astrocyte development.     

Formation and remodeling of the brain extracellular matrix in neural plasticity: Roles of chondroitin sulfate and hyaluronan

BackgroundThe extracellular matrix (ECM) of the brain is rich in glycosaminoglycans such as chondroitin sulfate (CS) and hyaluronan. These glycosaminoglycans are organized into either diffuse or condensed ECM. Diffuse ECM is distributed throughout the brain and fills perisynaptic spaces, whereas condensed ECM selectively surrounds parvalbumin-expressing inhibitory neurons (PV cells) in mesh-like structures called perineuronal nets (PNNs). The brain ECM acts as a non-specific physical barrier that modulates neural plasticity and axon regeneration.Scope of reviewHere, we review recent progress in understanding of the molecular basis of organization and remodeling of the brain ECM, and the involvement of several types of experience-dependent neural plasticity, with a particular focus on the mechanism that regulates PV cell function through specific interactions between CS chains and their binding partners. We also discuss how the barrier function of the brain ECM restricts dendritic spine dynamics and limits axon regeneration after injury.Major conclusionsThe brain ECM not only forms physical barriers that modulate neural plasticity and axon regeneration, but also forms molecular brakes that actively controls maturation of PV cells and synapse plasticity in which sulfation patterns of CS chains play a key role. Structural remodeling of the brain ECM modulates neural function during development and pathogenesis.General significanceGenetic or enzymatic manipulation of the brain ECM may restore neural plasticity and enhance recovery from nerve injury.This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa.     

The biochemical anatomy of cortical inhibitory synapses

Classical electron microscopic studies of the mammalian brain revealed two major classes of synapses, distinguished by the presence of a large postsynaptic density (PSD) exclusively at type 1, excitatory synapses. Biochemical studies of the PSD have established the paradigm of the synapse as a complex signal-processing machine that controls synaptic plasticity. We report here the results of a proteomic analysis of type 2, inhibitory synaptic complexes isolated by affinity purification from the cerebral cortex. We show that these synaptic complexes contain a variety of neurotransmitter receptors, neural cell-scaffolding and adhesion molecules, but that they are entirely lacking in cell signaling proteins. This fundamental distinction between the functions of type 1 and type 2 synapses in the nervous system has far reaching implications for models of synaptic plasticity, rapid adaptations in neural circuits, and homeostatic mechanisms controlling the balance of excitation and inhibition in the mature brain.     

Astrocytic Ephrin-B1 Regulates Synapse Remodeling Following Traumatic Brain Injury

Traumatic brain injury (TBI) can result in tissue alterations distant from the site of the initial injury, which can trigger pathological changes within hippocampal circuits and are thought to contribute to long-term cognitive and neuropsychological impairments. However, our understanding of secondary injury mechanisms is limited. Astrocytes play an important role in brain repair after injury and astrocyte-mediated mechanisms that are implicated in synapse development are likely important in injury-induced synapse remodeling. Our studies suggest a new role of ephrin-B1, which is known to regulate synapse development in neurons, in astrocyte-mediated synapse remodeling following TBI. Indeed, we observed a transient upregulation of ephrin-B1 immunoreactivity in hippocampal astrocytes following moderate controlled cortical impact model of TBI. The upregulation of ephrin-B1 levels in hippocampal astrocytes coincided with a decline in the number of vGlut1-positive glutamatergic input to CA1 neurons at 3 days post injury even in the absence of hippocampal neuron loss. In contrast, tamoxifen-induced ablation of ephrin-B1 from adult astrocytes in ephrin-B1^loxP/yERT2-Cre^GFAP mice accelerated the recovery of vGlut1-positive glutamatergic input to CA1 neurons after TBI. Finally, our studies suggest that astrocytic ephrin-B1 may play an active role in injury-induced synapse remodeling through the activation of STAT3-mediated signaling in astrocytes. TBI-induced upregulation of STAT3 phosphorylation within the hippocampus was suppressed by astrocyte-specific ablation of ephrin-B1 in vivo, whereas the activation of ephrin-B1 in astrocytes triggered an increase in STAT3 phosphorylation in vitro. Thus, regulation of ephrin-B1 signaling in astrocytes may provide new therapeutic opportunities to aid functional recovery after TBI.     

Regulation of Dendrite and Spine Morphogenesis and Plasticity by Catenins

The appropriate regulation of dendrite, spine, and synapse morphogenesis in neurons both during and after development is critical for the formation and maintenance of neural circuits. It is becomingly increasingly clear that the cadherin–catenin cell adhesion complex, a complex that has been widely studied in epithelia, regulates neuronal morphogenesis. More interestingly, the catenins, cytosolic proteins that bind to cadherins, regulate multiple aspects of neuronal morphogenesis including dendrite, spine, and synapse morphogenesis and plasticity, both independent of and dependent on their ability to bind cadherins. In this review, we examine some of the more recent and exciting studies that implicate individual catenins in various aspects of neuronal morphogenesis and plasticity.     

Synapse-to-nucleus signaling

Signals generated in distal subcellular compartments of neurons must often travel long distances to the nucleus to trigger changes in gene expression. This retrograde signaling is critical to the development, function, and survival of neural circuits, and neurons have evolved multiple mechanisms to transmit signals over long distances. In this review, we briefly summarize the range of mechanisms whereby distally generated signals are transported to neuronal nuclei. We then focus on the transport of soluble signals from the synapse to the nucleus during neuronal plasticity.     

The classic cadherins in synaptic specificity

During brain development, billions of neurons organize into highly specific circuits. To form specific circuits, neurons must build the appropriate types of synapses with appropriate types of synaptic partners while avoiding incorrect partners in a dense cellular environment. Defining the cellular and molecular rules that govern specific circuit formation has significant scientific and clinical relevance because fine scale connectivity defects are thought to underlie many cognitive and psychiatric disorders. Organizing specific neural circuits is an enormously complicated developmental process that requires the concerted action of many molecules, neural activity, and temporal events. This review focuses on one class of molecules postulated to play an important role in target selection and specific synapse formation: the classic cadherins. Cadherins have a well-established role in epithelial cell adhesion, and although it has long been appreciated that most cadherins are expressed in the brain, their role in synaptic specificity is just beginning to be unraveled. Here, we review past and present studies implicating cadherins as active participants in the formation, function, and dysfunction of specific neural circuits and pose some of the major remaining questions.     

The classic cadherins in synaptic specificity

During brain development, billions of neurons organize into highly specific circuits. To form specific circuits, neurons must build the appropriate types of synapses with appropriate types of synaptic partners while avoiding incorrect partners in a dense cellular environment. Defining the cellular and molecular rules that govern specific circuit formation has significant scientific and clinical relevance because fine scale connectivity defects are thought to underlie many cognitive and psychiatric disorders. Organizing specific neural circuits is an enormously complicated developmental process that requires the concerted action of many molecules, neural activity, and temporal events. This review focuses on one class of molecules postulated to play an important role in target selection and specific synapse formation: the classic cadherins. Cadherins have a well-established role in epithelial cell adhesion, and although it has long been appreciated that most cadherins are expressed in the brain, their role in synaptic specificity is just beginning to be unraveled. Here, we review past and present studies implicating cadherins as active participants in the formation, function, and dysfunction of specific neural circuits and pose some of the major remaining questions.     

CYY-1/cyclin Y and CDK-5 differentially regulate synapse elimination and formation for rewiring neural circuits

The assembly and maturation of neural circuits require a delicate balance between synapse formation and elimination. The cellular and molecular mechanisms that coordinate synaptogenesis and synapse elimination are poorly understood. In C. elegans, DD motoneurons respecify their synaptic connectivity during development by completely eliminating existing synapses and forming new synapses without changing cell morphology. Using loss- and gain-of-function genetic approaches, we demonstrate that CYY-1, a cyclin box-containing protein, drives synapse removal in this process. In addition, cyclin-dependent kinase-5 (CDK-5) facilitates new synapse formation by regulating the transport of synaptic vesicles to the sites of synaptogenesis. Furthermore, we show that coordinated activation of UNC-104/Kinesin3 and Dynein is required for patterning newly formed synapses. During the remodeling process, presynaptic components from eliminated synapses are recycled to new synapses, suggesting that signaling mechanisms and molecular motors link the deconstruction of existing synapses and the assembly of new synapses during structural synaptic plasticity.     

A Tribute to Mary C. McKenna: Glutamate as Energy Substrate and Neurotransmitter—Functional Interaction Between Neurons and Astrocytes

Glutamate metabolism in the brain is extremely complex not only involving a large variety of enzymes but also a tight partnership between neurons and astrocytes, the latter cells being in control of de novo synthesis of glutamate. This review provides an account of the processes involved, i.e. pyruvate carboxylation and recycling as well as the glutamate–glutamine cycle, focusing on the many seminal contributions from Dr. Mary McKenna. The ramification of the astrocytic end feet allowing contact and control of hundreds of thousands of synapses at the same time obviously puts these cells in a prominent position to regulate neural activity. Additionally, the astrocytes take active part in the neurotransmission processes by releasing a variety of gliotransmitters including glutamate. Hence, the term “the tripartite synapse”, in which there is an active and dynamic interplay between the pre- and post-synaptic neurons and the ensheathing astrocytes, has been coined. The studies of Mary McKenna and her colleagues over several decades have been of paramount importance for the elucidation of compartmentation in astrocytes and synaptic terminals and the intricate metabolic processes underlying the glutamatergic neurotransmission process.     

Two-step wiring plasticity--a mechanism for estrogen-induced rewiring of cortical circuits

Estrogens have been shown to exert powerful effects on cognitive behaviors mediated by several areas of the brain including the cortex. Remodeling of spiny synapses is a key step in the rewiring of neuronal circuitry thought to underlie the processing and storage of information in the forebrain. Whereas estrogen has been shown to regulate synapse structure and function, we are only just starting to understand the molecular and cellular underpinnings of how estrogens can modulate neuronal circuits. Here I will review recent molecular and cellular work that offers a potential mechanism of how estrogen may modulate synapse structure and function of cortical neurons. This mechanism allows cortical neurons to respond to activity-dependent stimuli with greater efficacy in a cellular model termed "Two-Step Wiring Plasticity". This novel form of spine plasticity thus provides insight into how estrogens may modulate the rewiring of neuronal circuits, underlying its ability to influencing cortically based behaviors. This article is part of a Special Issue entitled 'Neurosteroids'.     

Central and Peripheral Cytokines Mediate Immune-Brain Connectivity

The immune system is a homeostatic system that contributes to maintain the constancy of the molecular and cellular components of the organism. Immune cells can detect the intrusion of foreign antigens or alteration of self-components and send information to the central nervous system (CNS) about this kind of perturbations, acting as a receptor sensorial organ. The brain can respond to such signals by emitting neuro/endocrine signals capable of affecting immune reactivity. Thus, the immune system, as other physiologic systems, is under brain control. Under disease conditions, when priorities for survival change, the immune system can, within defined limits, reset brain-integrated neuro-endocrine mechanisms in order to favour immune processes at the expenses of other physiologic systems. In addition, some cytokines initially conceived as immune products, such as IL-1 and IL-6, are also produced in the “healthy” brain by glial cells and even by some neurons. These and other cytokines have the capacity to affect synaptic plasticity acting as mediators of interactions between astrocytes and pre- and post-synaptic neurons that constitute what is actually defined as a tripartite synapse. Since the production of cytokines in the brain is affected by peripheral immune and central neural signals, it is conceivable that tripartite synapses can, in turn, serve as a relay system in immune-CNS communication.