Studies on various animal models have established that neuronal activity can influence the myelination process. Are such mechanisms present in humans, and do they mediate experience-driven white matter plasticity not only during early development but also in adolescents and adults? While there is as yet no direct evidence for this, a number of findings – reviewed here – are consistent with this idea. First, postmortem and neuroimaging studies show that the human white matter development is a protracted process that continues well into adulthood. Second, developmental changes and individual differences in white matter structure are related to differences in neural activity and behavior. Finally, studies on effects of long-term training, in particular in musicians, show strong relations between training and white matter structure. I conclude by briefly discussing possible types of white matter plasticity that could underlie these findings, emphasizing a distinction between indirect myelination plasticity, where the myelin sheath grows in parallel with the axon itself, and direct myelination plasticity, where the myelin sheath thickness is modulated independently of axonal diameter.

Neuronal networks can adapt to global changes in activity levels through compensatory modifications in pre- and postsynaptic parameters of synaptic transmission. These forms of synaptic plasticity are known as synaptic homeostasis, and are thought to require specific cellular interactions and signaling across the entire neuronal network. However, the molecular mechanisms underlying synaptic homeostasis have so far been investigated mostly in primary cultures of dissociated neurons, a preparation that lacks the specificity of in vivo circuitry. Here, we show that there are critical differences in the properties of synaptic homeostasis between dissociated neuronal cultures and organotypic slices, a preparation that preserves more precisely in vivo connectivity. Moreover, the cell adhesion molecule β3 integrin, which regulates excitatory synaptic strength, is specifically required for a postsynaptic form of synaptic homeostasis called synaptic scaling in both dissociated cultures and organotypic slices. Conversely, another form of synaptic homeostasis that involves changes in presynaptic quantal content occurs independently of β3 integrin. Our findings define the differential involvement of β3 integrin in two forms of synaptic homeostasis.

In this review, we discuss examples that show how glial-cell pathology is increasingly recognized in several neurodegenerative diseases. We also discuss the more provocative idea that some of the disorders that are currently considered to be neurodegenerative diseases might, in fact, be due to primary abnormalities in glia. Although the mechanism of glial pathology (i.e. modulating glutamate excitotoxicity) might be better established for amyotrophic lateral sclerosis (ALS), a role for neuronal–glial interactions in the pathogenesis of most neurodegenerative diseases is plausible. This burgeoning area of neuroscience will receive much attention in the future and it is expected that further understanding of basic neuronal–glial interactions will have a significant impact on the understanding of the fundamental nature of human neurodegenerative disorders.

Satellite glial cells (SGCs) are specialized cells that form a tight sheath around neurons in sensory ganglia. In recent years, there is increasing interest in SGCs and they have been studied in both intact ganglia and in tissue culture. Here we studied phenotypic changes in SGCs in cultured trigeminal ganglia from adult mice, containing both neurons and SGCs, using phase optics, immunohistochemistry and time-lapse photography. Cultures were followed for up to 14 days. After isolation virtually every sensory neuron is ensheathed by SGCs, as in the intact ganglia. After one day in culture, SGCs begin to migrate away from their parent neurons, but in most cases the neurons still retain an intact glial cover. At later times in culture, there is a massive migration of SGCs away from the neurons and they undergo clear morphological changes, and at 7 days they become spindle-shaped. At one day in culture SGCs express the glial marker glutamine synthetase, and also the purinergic receptor P2X7. From day 2 in culture the glutamine synthetase expression is greatly diminished, whereas that of P2X7 is largely unchanged. We conclude that SGCs retain most of their characteristics for about 24 h after culturing, but undergo major phenotypic changes at later times.

Astroglia are known to potentiate individual synapses, but their contribution to networks is unclear. Here we examined the effect of adding either astroglia or media conditioned by astroglia on entire networks of rat hippocampal neurons cultured on microelectrode arrays. Added astroglia increased spontaneous spike rates nearly two-fold and glutamate-stimulated spiking by six-fold, with desensitization eliminated for bath addition of 25 μM glutamate. Astrocyte-conditioned medium partly mimicked the effects of added astroglia. Bursting behavior was largely unaffected by added astroglia except with added glutamate. Addition of the GABAA receptor antagonist bicuculline also increased spike rates but with more subtle differences between networks without or with added astroglia. This indicates that networks without added astroglia were inhibited greatly. In all conditions, the log–log distribution of spike rates fit well to linear distributions over three orders of magnitude. Networks with added astroglia shifted consistently toward higher spike rates. Immunostaining for GFAP revealed a linear increase with added astroglia, which also increased neuronal survival. The increased spike rates with added astroglia correlated with a 1.7-fold increase in immunoreactive synaptophysin puncta, and increases of six-fold for GABAAβ, two-fold for NMDA-R1 and two-fold for Glu-R1 puncta, with receptor clustering that indicated synaptic scaling. Together, these results indicate that added astroglia increase the density of synapses and receptors, and facilitate higher spike rates for many elements in the network. These effects are reproduced by glia-conditioned media, with the exception of glutamate-mediated transmission.

The migration of oligodendrocyte precursor cells (OPCs) is modulated by secreted molecules in their environment and by cell–cell and matrix–cell interactions. Here, we ask whether membrane-anchored guidance cues, such as the ephrin ligands and their Eph receptors, participate in the control of OPC migration in the optic nerve. We postulate that EphA and EphB receptors, which are expressed on axons of retinal ganglion cells, interact with ephrins on the surface of OPCs. We show the expression of ephrinA5, ephrinB 2 and ephrinB3 in the migrating OPCs of the optic nerve as well as in the diencephalic sites from where they originate. In addition, we demonstrate that coated EphB2-Fc receptors, which are specific for ephrinB2/B3 ligands, induce dramatic changes in the contact and migratory properties of OPCs, indicating that axonal EphB receptors activate ephrinB signaling in OPCs. Based on these findings, we propose that OPCs are characterized by an ephrin code, and that Eph–ephrin interactions between axons and OPCs control the distribution of OPCs in the optic axonal tracts, and the progress and arrest of their migration.

We provide both molecular and pharmacological evidence that the metabotropic, purinergic, P2Y6, P2Y12 and P2Y13 receptors and the ionotropic P2X4 receptor contribute strongly to the rapid calcium response caused by ATP and its analogues in mouse microglia. Real-time PCR demonstrates that the most prevalent P2 receptor in microglia is P2Y6 followed, in order, by P2X4, P2Y12, and P2X7 = P2Y13. Only very small quantities of mRNA for P2Y1, P2Y2, P2Y4, P2Y14, P2X3 and P2X5 were found. Dose-response curves of the rapid calcium response gave a potency order of: 2MeSADP>ADP=UDP=IDP=UTP>ATP>BzATP, whereas A2P4 had little effect. Pertussis toxin partially blocked responses to 2MeSADP, ADP and UDP. The P2X4 antagonist suramin, but not PPADS, significantly blocked responses to ATP. These data indicate that P2Y6, P2Y12, P2Y13 and P2X receptors mediate much of the rapid calcium responses and shape changes in microglia to low concentrations of ATP, presumably at least partly because ATP is rapidly hydrolyzed to ADP. Expression of P2Y6, P2Y12 and P2Y13 receptors appears to be largely glial in the brain, so that peripheral immune cells and CNS microglia share these receptors. Thus, purinergic, metabotropic, P2Y6, P2Y12, P2Y13 and P2X4 receptors might share a role in the activation and recruitment of microglia in the brain and spinal cord by widely varying stimuli that cause the release of ATP, including infection, injury and degeneration in the CNS, and peripheral tissue injury and inflammation which is signaled via nerve signaling to the spinal cord.

To ensure rapid and efficient impulse conduction, myelinated axons establish and maintain specific protein domains. For instance, sodium (Na+) channels accumulate in the node of Ranvier; potassium (K+) channels aggregate in the juxtaparanode and neurexin/caspr/paranodin clusters in the paranode. Our understanding of the mechanisms that control the initial clustering of these proteins is limited and less is known about domain maintenance. Correlative data indicate that myelin formation and/or mature myelin-forming cells mediate formation of all three domains. Here, we test whether myelin is required for maintaining Na+ channel domains in the nodal gap by employing two demyelinating murine models: (1) cuprizone ingestion, which induces complete demyelination through oligodendrocyte toxicity; and (2) ceramide galactosyltransferase deficient mice, which undergo spontaneous adult-onset demyelination without oligodendrocyte death. Our data indicate that the myelin sheath is essential for long-term maintenance of sodium channel domains; however, oligodendrocytes, independent of myelin, provide a partial protective influence on the maintenance of nodal Na+ channel clusters. Thus, we propose that multiple mechanisms regulate the maintenance of nodal protein organization. Finally, we present evidence that following the loss of Na+ channel clusters the chronological progression of expression and reclustering of Na+ channel isoforms during the course of CNS remyelination recapitulates development.

Mitochondria and other membranous organelles are frequently enriched in the nodes and paranodes of peripheral myelinated axons, particularly of large caliber axons. The physiological role(s) of this organelle enrichment and the rheologic factors that regulate it are not well understood. Previous studies indicate that axonal transport of organelles across the nodal/paranodal region is regulated locally. In this study, we have examined the ultrastructure of myelinated axons in the sciatic nerves of mice deficient in contactin-associated protein (Caspr), an integral junctional component. These mice, which lack the normal septate-like junctions that promote attachment of the glial (paranodal) loops to the axon, contain aberrant mitochondria in their nodal/paranodal regions. Typically, these mitochondria are large, swollen and occupy prominent varicosities of the nodal axolemma. In contrast, mitochondria outside the nodal/paranodal regions of the myelinated axons appear normal. These findings suggest that paranodal junctions regulate mitochondrial transport and function in the axoplasm of the nodal/paranodal region of myelinated axons of peripheral nerves. They further indicate that paranodal junctions might have a role, either direct or indirect, in the local regulation of energy metabolism in the nodal region.

Early in development, steroid hormones structurally organize various regions of the CNS. However, steroid hormones continue to affect the structure and function of the CNS throughout the life of the individual. In this review, we discuss sex differences and similarities in steroid-induced synaptic plasticity in the adult brain. Particular emphasis is placed on steroid-induced plasticity in the hippocampus, a brain region important in learning and memory. This topic is relevant to the growing evidence for the actions of sex hormones outside of the reproductive neuroendocrine axis. It also tells an important and emerging story about non-genomic and genomic actions of steroids at the cellular and molecular levels. Specifically, the effects of estrogen and progesterone as well as the androgens and glucocorticoids are discussed. The influence of steroids on hippocampal structure and function can differ vastly between the sexes. However, there are certain similarities that might aid in our understanding of how steroids affect CNS plasticity in general. Although future studies will undoubtedly lead us to a greater understanding of these phenomena, the data reviewed indicate that when studying synaptic plasticity, the sex and hormonal milieu of the individual might significantly influence the outcome and interpretation of the research.

The c-MYC protooncogene is overexpressed in the most malignant primary brain tumor, glioblastoma multiforme (GBM), and has been correlated with the undifferentiated character of several cell types. However, the role of Myc activity in the generation of GBMs is not known. In this report, we show that gene transfer of c-MYC to GFAP-expressing astrocytes in vitro promotes the outgrowth of GFAP-negative, nestin-expressing cells with progenitor-like morphology, growth characteristics and gene-expression pattern. In addition, gene transfer of c-MYC to GFAP-expressing astrocytes in vivo induces GBMs when co-expressed with activated Ras and Akt. Without c-MYC, Ras+Akt induces GBMs from nestin-expressing CNS progenitors but is insufficient in GFAP-expressing differentiated astrocytes. The ability of Myc activity to enhance the oncogenic effects of Ras+Akt appears to be limited to GFAP-expressing astrocytes because nestin-expressing progenitors show no increase in GBM formation with the addition of MYC to Ras+Akt. These studies indicate that one role of MYC activity in the formation of gliomas might be to either promote or reinforce an undifferentiated phenotype required for glioma cells to respond to the oncogenic effects of elevated Ras and Akt activity.

Myelin formation and maintenance depends on the establishment of two structurally and biochemically discernible domains: (a) compact myelin, that is multilamellar stacks of plasma membrane sheets; and (b) cytoplasmic channels that border the compact myelin domains, attach them to the cell body and anchor the myelin sheath to the axonal membrane. To identify proteins involved in the organization of these domains we took advantage of the high lipid content of compact myelin to separate it cleanly from other neural membranes and then used reverse-phase HPLC coupled to Electro-Spray Double Mass Spectrometry (‘MudPIT’) to characterize the proteome of this sample. MudPIT allowed us to sidestep the bias of 2D-PAGE against either highly charged or transmembrane proteins. Thus, of 97 proteins that presented at least two, fully tryptic peptides (a stringent threshold), seven were well known myelin markers, including the mayor CNS myelin proteins: proteolipid protein and myelin basic protein, which are not resolvable by 2D-PAGE. Furthermore, we have confirmed and extended the known compact myelin proteome by 22 proteins and confirmed that CNS and PNS myelinated tracts present Sirtuin 2, a tubulin deacetylase, and Septin 7, a small GTPase that is likely to be involved in membrane and cytoplasm partitioning.

Given the growing body of evidence for a role of glia in pain modulation, it is plausible that the exaggerated visceral pain in chronic conditions might be regulated by glial activation. In this study, we have investigated a possible role for microglia in rats with chronic visceral hypersensitivity and previously documented altered neuronal function. Experiments were performed on adult male Sprague-Dawley rats pre-treated with neonatal colon irritation (CI) and on control rats. Effects of fractalkine (FKN, a chemokine involved in neuron-to-microglia signaling) and of minocycline (an inhibitor of microglia) on visceral sensitivity were examined. Visceral sensitivity was assessed by recording the electromyographic (EMG) responses to graded colorectal distension (CRD) in mildly sedated rats. Responses to CRD were recorded before and after injection of FKN, minocycline or vehicle. Somatic thermal hyperalgesia was measured by latency of paw withdrawal to radiant heat. The pattern and intensity of microglial distribution at L6–S2 in the spinal cord was also compared in rats with CI and controls by fluorescence microscopy using OX-42. Results show that: (1) FKN significantly facilitated EMG responses to noxious CRD by >52% in control rats. FKN also induced thermal hyperalgesia in control rats, consistent with previous reports; (2) minocycline significantly inhibited EMG responses to noxious CRD by >70% in rats with CI compared to controls 60 min after injection. The anti-nociceptive effect of minocycline lasted for 180 min in rats with CI, reaching peak values 60 min after injection. Our results show that FKN enhances visceral and somatic nociception, whereas minocycline inhibits visceral hypersensitivity in chronically sensitized rats, which indicates a role for microglia in visceral hypersensitivity.

The evolutionary origin of myelinating cells in the vertebrate nervous system remains a mystery. A clear delineation of the developmental potentialities of neuronal support cells in the CNS and PNS might aid in formulating a hypothesis about the origins of myelinating cells. Although a glial-precursor cell in the CNS can differentiate into oligodendrocytes (OLs), Schwann cells (SCs) and astrocytes, a homologous multipotential cell has not yet been found in the PNS. Here, we identify a cell type of embryonic dorsal root ganglia (DRG) of the PNS – the satellite cell – that develops into OLs, SCs and astrocytes. Interestingly, satellite-cell-derived OL precursors were found in cultures prepared from embryonic day 17 (E17) to postnatal day 8 (P8) ganglia, but not from adult DRGs, revealing a narrow developmental window for multipotentiality. We suggest that compromising the organization of the ganglia triggers a differentiation pathway in a subpopulation of satellite cells, inducing them to become myelinating cells with either a CNS or PNS phenotype. Our data provide an additional, novel piece in the myelinating-cell-precursor puzzle, and lead to the concept that cells in the CNS and PNS that function to ensheath neuronal cell bodies and axons can differentiate into OLs, SCs and astrocytes. In sum, it appears that glial fate might be determined over and above the CNS/PNS dichotomy. Last, we suggest that primordial ensheathing cells form the original cell population in which the myelination program first evolved.

Low-density-lipoprotein receptors (LDLRs) are an evolutionarily ancient surface protein family with the ability to activate a diversity of extracellular signals across the cellular membrane in the adult central nervous system (CNS). Their intimate roles in modulating synaptic plasticity and their necessity in hippocampal-dependent learning and memory have only recently come to light. Two known LDLR ligands, specifically apolipoprotein E (apoE) and reelin, have been the most widely investigated in this regard. Most of our understanding of synaptic plasticity comes from investigation of both pre- and postsynaptic alterations. Therefore, it is interesting to note that neurons and glia that do not contribute to the synaptic junction in question can secrete signaling molecules that affect synaptic plasticity. Notably, reelin and apoE have been shown to modulate hippocampal long-term potentiation in general, and affect NMDA receptor and AMPA receptor regulation specifically. Furthermore, these receptors and signaling molecules have significant roles in neuronal degenerative diseases such as Alzheimer's disease. The recent production of recombinant proteins, knockout and transgenic mice for receptors and ligands and the development of human ApoE targeted replacement mice have significantly expanded our understanding of the roles LDLRs and their ligands have in certain disease states and the accompanying initiation of specific signaling pathways. This review describes the role LDLRs, apoE and reelin have in the regulation of hippocampal synaptic plasticity.

Autism spectrum disorders (ASDs) including classic autism is a group of complex developmental disabilities with core deficits of impaired social interactions, communication difficulties and repetitive behaviors. Although the neurobiology of ASDs has attracted much attention in the last two decades, the role of microglia has been ignored. Existing data are focused on their recognized role in neuroinflammation, which only covers a small part of the pathological repertoire of microglia. This review highlights recent findings on the broader roles of microglia, including their active surveillance of brain microenvironments and regulation of synaptic connectivity, maturation of brain circuitry and neurogenesis. Emerging evidence suggests that microglia respond to pre- and postnatal environmental stimuli through epigenetic interface to change gene expression, thus acting as effectors of experience-dependent synaptic plasticity. Impairments of these microglial functions could substantially contribute to several major etiological factors of autism, such as environmental toxins and cortical underconnectivity. Our recent study on Rett syndrome, a syndromic autistic disorder, provides an example that intrinsic microglial dysfunction due to genetic and epigenetic aberrations could detrimentally affect the developmental trajectory without evoking neuroinflammation. We propose that ASDs provide excellent opportunities to study the influence of microglia on neurodevelopment, and this knowledge could lead to novel therapies.

There is increasing evidence that severe mood disorders are associated with impairment of structural plasticity and cellular resilience. Cumulative data demonstrate that mood stabilizers regulate intracellular signaling cascades, including protein kinase C (PKC), PKA, mitogen-activated protein (MAP) kinase, glycogen synthase kinase 3-β (GSK3-β) and intracellular calcium, which are signaling pathways that regulate synaptic plasticity. In this context, it is noteworthy that a growing body of data indicates that the glutamatergic system, has a major role in neuronal plasticity and cellular resilience, might be involved in the pathophysiology and treatment of mood disorders. AMPA glutamate-receptor trafficking is important in synaptic plasticity and might play crucial roles in maintaining critical neuronal circuits associated with mood. Two clinically effective, structurally dissimilar, antimanic agents, lithium and valproate (VPA), down-regulate synaptic expression of AMPA receptor subunit GluR1 in hippocampus in chronically treated rats. This reduction in synaptic GluR1 by lithium and VPA is due to attenuated phosphorylation of GluR1 at a specific PKA site (residue 845 of GluR1), which is crucial for AMPA receptor insertion. By contrast, imipramine, which can provoke mania, increases synaptic expression of GluR1 in the hippocampus in vivo. Furthermore, there is ample evidence from preclinical and clinical research that the glutamatergic system is involved in the pathophysiology of mood disorders and that many of the somatic treatments used for mood disorders including antidepressants, mood stabilizers, atypical antipsychotic drugs and electroconvulsive therapy have both direct and indirect effects on the glutamatergic system. Given these findings, further research with medications that specifically affect the glutamatergic system is warranted. Recent studies in our lab have shown that riluzole, a FDA approved medicine that regulates the glutamatergic system, shows antidepressant efficacy in unipolar and bipolar depression. These studies indicate that regulation of glutamate-mediated synaptic plasticity might play a role in the treatment of mood disorders, and raise new avenues for novel therapies for this devastating illness.

Cultures of Schwann cells from neonatal rat sciatic nerves were treated with acetylcholine agonists and the effects on cell proliferation evaluated. 3[H]-thymidine incorporation shows that acetylcholine (ACh) receptor agonists inhibit cell proliferation, and FACS analysis demonstrates cell-cycle arrest and accumulation of cells in the G1 phase. The use of arecaidine, a selective agonist of muscarinic M2 receptors reveals that this effect depends mainly on M2 receptor activation. The arecaidine dependent-block in G1 is reversible because removal of arecaidine from the culture medium induces progression to the S phase. The block of the G1-S transition is also characterized by modulation of the expression of several cell-cycle markers. Moreover, treatment with ACh receptor agonist causes both a decrease in the PCNA protein levels in Schwann cell nuclei and an increase in p27 and p53 proteins. Finally, immuno-electron microscopy demonstrates that M2 receptors are expressed by Schwann cells in vivo. These results indicate that ACh, by modulating Schwann cell proliferation through M2 receptor activation, might contribute to their progression to a more differentiated phenotype.

Cells that express the NG2 chondroitin sulfate proteoglycan and platelet-derived growth factor receptor alpha (NG2 glia) are widespread in the adult human cerebral cortex and white matter and represent 10–15% of non-neuronal cells. The morphology and distribution of NG2 glia are similar to, but distinct from, both microglia and astrocytes. They are present as early as 17 weeks gestation and persist throughout life. NG2 glia can be detected in a variety of human central nervous system (CNS) diseases, of which multiple sclerosis is the best studied. NG2 glia show morphological changes in the presence of pathology and can show expression of the Ki-67 proliferation antigen. The antigenic profile and morphology of NG2 glia in human tissues are consistent with an oligodendrocyte progenitor function that has been well established in rodent models. Most antibodies to NG2 do not stain formalin-fixed paraffin-embedded tissues. Advances in our understanding of NG2 glia in human tissues will require the development of more robust markers for their detection in routinely processed human specimens.

Astrocytes constitute a major group of glial cells which were long regarded as passive elements, fulfilling nutritive and structural functions for neurons. Calcium rise in astrocytes propagating to neurons was the first demonstration of direct interaction between the two cell types. Since then, calcium has been widely used, not only as an indicator of astrocytic activity but also as a stimulator switch to control astrocyte physiology. As a result, astrocytes have been elevated from auxiliaries to neurons, to cells involved in processing synaptic information. Curiously, while there is evidence that astrocytes play an important role in synaptic plasticity, the data relating to calcium's pivotal role are inconsistent. In this review, we will detail the various mechanisms of calcium flux in astrocytes, then briefly present the calcium-dependent mechanisms of gliotransmitter release. Finally, we will discuss the role of calcium in plasticity and present alternative explanations that could reconcile the conflicting results published recently.