D-ꞵ-hydroxybutyrate stabilizes hippocampal CA3-CA1 circuit during acute insulin resistance.

The brain primarily relies on glycolysis for mitochondrial respiration but switches to alternative fuels such as ketone bodies (KBs) when less glucose is available. Neuronal KB uptake, which does not rely on glucose transporter 4 (GLUT4) or insulin, has shown promising clinical applicability in alleviating the neurological and cognitive effects of disorders with hypometabolic components. However, the specific mechanisms by which such interventions affect neuronal functions are poorly understood. In this study, we pharmacologically blocked GLUT4 to investigate the effects of exogenous KB D-ꞵ-hydroxybutyrate (D-ꞵHb) on mouse brain metabolism during acute insulin resistance (AIR). We found that both AIR and D-ꞵHb had distinct impacts across neuronal compartments: AIR decreased synaptic activity and long-term potentiation (LTP) and impaired axonal conduction, synchronization, and action potential properties, while D-ꞵHb rescued neuronal functions associated with axonal conduction, synchronization, and LTP.

D-ß-hydroxybutyrate stabilizes hippocampal CA3-CA1 circuit during acute insulin resistance.

1.The brain primarily relies on glycolysis for mitochondrial respiration but switches to alternative fuels such as ketone bodies (KBs) when less glucose is available. Neuronal KB uptake, which does not rely on glucose transporter 4 (GLUT4) or insulin, has shown promising clinical applicability in alleviating the neurological and cognitive effects of disorders with hypometabolic components. However, the specific mechanisms by which such interventions affect neuronal functions are poorly understood. In this study, we pharmacologically blocked GLUT4 to investigate the effects of exogenous KB D-P-hydroxybutyrate (D-ßHb) on mouse brain metabolism during acute insulin resistance (AIR). We found that both AIR and D-ßHb had distinct impacts across neuronal compartments: AIR decreased synaptic activity and long-term potentiation (LTP) and impaired axonal conduction, synchronization, and action potential (AP) properties, while D- PHb rescued neuronal functions associated with axonal conduction, synchronization and LTP.

Understanding the Role of the Glial Scar through the Depletion of Glial Cells after Spinal Cord Injury.

Spinal cord injury (SCI) is a condition that affects between 8.8 and 246 people in a million and, unlike many other neurological disorders, it affects mostly young people, causing deficits in sensory, motor, and autonomic functions. Promoting the regrowth of axons is one of the most important goals for the neurological recovery of patients after SCI, but it is also one of the most challenging goals. A key event after SCI is the formation of a glial scar around the lesion core, mainly comprised of astrocytes, NG2+-glia, and microglia. Traditionally, the glial scar has been regarded as detrimental to recovery because it may act as a physical barrier to axon regrowth and release various inhibitory factors. However, more and more evidence now suggests that the glial scar is beneficial for the surrounding spared tissue after SCI. Here, we review experimental studies that used genetic and pharmacological approaches to ablate specific populations of glial cells in rodent models of SCI in order to understand their functional role. The studies showed that ablation of either astrocytes, NG2+-glia, or microglia might result in disorganization of the glial scar, increased inflammation, extended tissue degeneration, and impaired recovery after SCI. Hence, glial cells and glial scars appear as important beneficial players after SCI.

Recent Insights into the Functional Role of AMPA Receptors in the Oligodendrocyte Lineage Cells In Vivo.

This review discusses the experimental findings of several recent studies which investigated the functional role of AMPA receptors (AMPARs) in oligodendrocyte lineage cells in vivo, in mice and in zebrafish. These studies provided valuable information showing that oligodendroglial AMPARs may be involved in the modulation of proliferation, differentiation, and migration of oligodendroglial progenitors, as well as survival of myelinating oligodendrocytes during physiological conditions in vivo. They also suggested that targeting the subunit composition of AMPARs may be an important strategy for treating diseases. However, at the same time, the experimental findings taken together still do not provide a clear picture on the topic. Hence, new ideas and new experimental designs are required for understanding the functional role of AMPARs in the oligodendrocyte lineage cells in vivo. It is also necessary to consider more closely the temporal and spatial aspects of AMPAR-mediated signalling in the oligodendrocyte lineage cells. These two important aspects are routinely discussed by neuronal physiologists studying glutamatergic synaptic transmission, but are rarely debated and thought about by researchers studying glial cells.

Technical approaches and challenges to study AMPA receptors in oligodendrocyte lineage cells: Past, present, and future.

Receptors for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPARs) are ligand-gated ionotropic receptors for glutamate that is a major excitatory neurotransmitter in the central nervous system. AMPARs are located at postsynaptic sites of neuronal synapses where they mediate fast synaptic signaling and synaptic plasticity. Remarkably, AMPARs are also expressed by glial cells. Their expression by the oligodendrocyte (OL) lineage cells is of special interest because AMPARs mediate fast synaptic communication between neurons and oligodendrocyte progenitor cells (OPCs), modulate proliferation and differentiation of OPCs, and may also be involved in regulation of myelination. On the other hand, during pathological conditions, AMPARs may mediate damage of the OL lineage cells. In the present review, we focus on the technical approaches that have been used to study AMPARs in the OL lineage cells, and discuss future perspectives of AMPAR research in these glial cells.

Altered Expression of Ion Channels in White Matter Lesions of Progressive Multiple Sclerosis: What Do We Know About Their Function?

Despite significant advances in our understanding of the pathophysiology of multiple sclerosis (MS), knowledge about contribution of individual ion channels to axonal impairment and remyelination failure in progressive MS remains incomplete. Ion channel families play a fundamental role in maintaining white matter (WM) integrity and in regulating WM activities in axons, interstitial neurons, glia, and vascular cells. Recently, transcriptomic studies have considerably increased insight into the gene expression changes that occur in diverse WM lesions and the gene expression fingerprint of specific WM cells associated with secondary progressive MS. Here, we review the ion channel genes encoding K+, Ca2+, Na+, and Cl- channels; ryanodine receptors; TRP channels; and others that are significantly and uniquely dysregulated in active, chronic active, inactive, remyelinating WM lesions, and normal-appearing WM of secondary progressive MS brain, based on recently published bulk and single-nuclei RNA-sequencing datasets. We discuss the current state of knowledge about the corresponding ion channels and their implication in the MS brain or in experimental models of MS. This comprehensive review suggests that the intense upregulation of voltage-gated Na+ channel genes in WM lesions with ongoing tissue damage may reflect the imbalance of Na+ homeostasis that is observed in progressive MS brain, while the upregulation of a large number of voltage-gated K+ channel genes may be linked to a protective response to limit neuronal excitability. In addition, the altered chloride homeostasis, revealed by the significant downregulation of voltage-gated Cl- channels in MS lesions, may contribute to an altered inhibitory neurotransmission and increased excitability.

Glutamate receptors and glutamatergic signalling in the peripheral nerves.

In the peripheral nervous system, the vast majority of axons are accommodated within the fibre bundles that constitute the peripheral nerves. Axons within the nerves are in close contact with myelinating glia, the Schwann cells that are ideally placed to respond to, and possibly shape, axonal activity. The mechanisms of intercellular communication in the peripheral nerves may involve direct contact between the cells, as well as signalling via diffusible substances. Neurotransmitter glutamate has been proposed as a candidate extracellular molecule mediating the cross-talk between cells in the peripheral nerves. Two types of experimental findings support this idea: first, glutamate has been detected in the nerves and can be released upon electrical or chemical stimulation of the nerves; second, axons and Schwann cells in the peripheral nerves express glutamate receptors. Yet, the studies providing direct experimental evidence that intercellular glutamatergic signalling takes place in the peripheral nerves during physiological or pathological conditions are largely missing. Remarkably, in the central nervous system, axons and myelinating glia are involved in glutamatergic signalling. This signalling occurs via different mechanisms, the most intriguing of which is fast synaptic communication between axons and oligodendrocyte precursor cells. Glutamate receptors and/or synaptic axon-glia signalling are involved in regulation of proliferation, migration, and differentiation of oligodendrocyte precursor cells, survival of oligodendrocytes, and re-myelination of axons after damage. Does synaptic signalling exist between axons and Schwann cells in the peripheral nerves? What is the functional role of glutamate receptors in the peripheral nerves? Is activation of glutamate receptors in the nerves beneficial or harmful during diseases? In this review, we summarise the limited information regarding glutamate release and glutamate receptors in the peripheral nerves and speculate about possible mechanisms of glutamatergic signalling in the nerves. We highlight the necessity of further research on this topic because it should help to understand the mechanisms of peripheral nervous system development and nerve regeneration during diseases.

Glutamatergic signaling between neurons and oligodendrocyte lineage cells: Is it synaptic or non-synaptic?

Fast chemical synaptic transmission is a major form of neuronal communication in the nervous system of mammals. Another important, but very different, form of intercellular communication is volume transmission, which is a slower non-synaptic signaling. The amino acid glutamate is the most abundant excitatory neurotransmitter in the nervous system, which mediates both synaptic and non-synaptic signaling via ionotropic and metabotropic glutamate receptors. Intriguingly, neurons establish glutamatergic synapses also with oligodendrocyte precursor cells (NG2+ -glia). Moreover, neuronal activity and glutamate receptors play an important role in the development and functionality of oligodendrocytes and their precursors in vivo. Yet, molecular characteristics and functional significance of neuron-glia synapses remain poorly understood, and it is unclear how glutamate receptors mediate the effects of neuronal activity on the oligodendrocyte lineage cells. In this review, we discuss what is known with regard to synaptic and non-synaptic glutamatergic signaling between neurons and oligodendrocyte lineage cells, what can be suggested based on the current state of knowledge, and what is fully unknown and requires new research.

In Vivo Regulation of Oligodendrocyte Precursor Cell Proliferation and Differentiation by the AMPA-Receptor Subunit GluA2.

The functional role of AMPA receptor (AMPAR)-mediated synaptic signaling between neurons and oligodendrocyte precursor cells (OPCs) remains enigmatic. We modified the properties of AMPARs at axon-OPC synapses in the mouse corpus callosum in vivo during the peak of myelination by targeting the GluA2 subunit. Expression of the unedited (Ca2+ permeable) or the pore-dead GluA2 subunit of AMPARs triggered proliferation of OPCs and reduced their differentiation into oligodendrocytes. Expression of the cytoplasmic C-terminal (GluA2(813-862)) of the GluA2 subunit (C-tail), a modification designed to affect the interaction between GluA2 and AMPAR-binding proteins and to perturb trafficking of GluA2-containing AMPARs, decreased the differentiation of OPCs without affecting their proliferation. These findings suggest that ionotropic and non-ionotropic properties of AMPARs in OPCs, as well as specific aspects of AMPAR-mediated signaling at axon-OPC synapses in the mouse corpus callosum, are important for balancing the response of OPCs to proliferation and differentiation cues.

Glutamate Activates AMPA Receptor Conductance in the Developing Schwann Cells of the Mammalian Peripheral Nerves.

Schwann cells (SCs) are myelinating cells of the PNS. Although SCs are known to express different channels and receptors on their surface, little is known about the activation and function of these proteins. Ionotropic glutamate receptors are thought to play an essential role during development of SC lineage and during peripheral nerve injury, so we sought to study their functional properties. We established a novel preparation of living peripheral nerve slices with preserved cellular architecture and used a patch-clamp technique to study AMPA-receptor (AMPAR)-mediated currents in SCs for the first time. We found that the majority of SCs in the nerves dissected from embryonic and neonatal mice of both sexes respond to the application of glutamate with inward current mediated by Ca2+-permeable AMPARs. Using stationary fluctuation analysis (SFA), we demonstrate that single-channel conductance of AMPARs in SCs is 8-11 pS, which is comparable to that in neurons. We further show that, when SCs become myelinating, they downregulate functional AMPARs. This study is the first to demonstrate AMPAR-mediated conductance in SCs of vertebrates, to investigate elementary properties of AMPARs in these cells, and to provide detailed electrophysiological and morphological characterization of SCs at different stages of development.SIGNIFICANCE STATEMENT We provide several important conceptual and technical advances in research on the PNS. We pioneer the first description of AMPA receptor (AMPAR)-mediated currents in the PNS glia of vertebrates and provide new insights into the properties of AMPAR channels in peripheral glia; for example, their Ca2+ permeability and single-channel conductance. We describe for the first time the electrophysiological and morphological properties of Schwann cells (SCs) at different stages of development and show that functional AMPARs are expressed only in developing, not mature, SCs. Finally, we introduce a preparation of peripheral nerve slices for patch-clamp recordings. This preparation opens new possibilities for studying the physiology of SCs in animal models and in surgical human samples.

Different patterns of neuronal activity trigger distinct responses of oligodendrocyte precursor cells in the corpus callosum.

In the developing and adult brain, oligodendrocyte precursor cells (OPCs) are influenced by neuronal activity: they are involved in synaptic signaling with neurons, and their proliferation and differentiation into myelinating glia can be altered by transient changes in neuronal firing. An important question that has been unanswered is whether OPCs can discriminate different patterns of neuronal activity and respond to them in a distinct way. Here, we demonstrate in brain slices that the pattern of neuronal activity determines the functional changes triggered at synapses between axons and OPCs. Furthermore, we show that stimulation of the corpus callosum at different frequencies in vivo affects proliferation and differentiation of OPCs in a dissimilar way. Our findings suggest that neurons do not influence OPCs in "all-or-none" fashion but use their firing pattern to tune the response and behavior of these nonneuronal cells.

N- and L-Type Voltage-Gated Calcium Channels Mediate Fast Calcium Transients in Axonal Shafts of Mouse Peripheral Nerve.

In the peripheral nervous system (PNS) a vast number of axons are accommodated within fiber bundles that constitute peripheral nerves. A major function of peripheral axons is to propagate action potentials along their length, and hence they are equipped with Na(+) and K(+) channels, which ensure successful generation, conduction and termination of each action potential. However little is known about Ca(2+) ion channels expressed along peripheral axons and their possible functional significance. The goal of the present study was to test whether voltage-gated Ca(2+) channels (VGCCs) are present along peripheral nerve axons in situ and mediate rapid activity-dependent Ca(2+) elevations under physiological circumstances. To address this question we used mouse sciatic nerve slices, Ca(2+) indicator Oregon Green BAPTA-1, and 2-photon Ca(2+) imaging in fast line scan mode (500 Hz). We report that transient increases in intra-axonal Ca(2+) concentration take place along peripheral nerve axons in situ when axons are stimulated electrically with single pulses. Furthermore, we show for the first time that Ca(2+) transients in peripheral nerves are fast, i.e., occur in a millisecond time-domain. Combining Ca(2+) imaging and pharmacology with specific blockers of different VGCCs subtypes we demonstrate that Ca(2+) transients in peripheral nerves are mediated mainly by N-type and L-type VGCCs. Discovery of fast Ca(2+) entry into the axonal shafts through VGCCs in peripheral nerves suggests that Ca(2+) may be involved in regulation of action potential propagation and/or properties in this system, or mediate neurotransmitter release along peripheral axons as it occurs in the optic nerve and white matter of the central nervous system (CNS).

Effects of the jimpy mutation on mouse retinal structure and function.

The Jimpy mutant mouse has a point mutation in the proteolipid protein gene (plp1). The resulting misfolding of the protein leads to oligodendrocyte death, myelin destruction, and failure to produce adequately myelinated axons in the central nervous system (CNS). It is not known how the absence of normal myelination during development influences neural function. We characterized the Jimpy mouse retina to find out whether lack of myelination in the optic nerve during development has an effect on normal functioning and morphology of the retina. Optokinetic reflex measurements showed that Jimpy mice had, in general, a functional visual system. Both PLP1 antibody staining and reverse transcriptase-polymerase chain reaction for plp1 mRNA showed that plp1 is not expressed in the wild-type retina. However, in the optic nerve, plp1 is normally expressed, and consequently, in Jimpy mutant mice, myelination of axons in the optic nerve was mostly absent. Nevertheless, neither axon count nor axon ultrastructure in the optic nerve was affected. Physiological recordings of ganglion cell activity using microelectrode arrays revealed a decrease of stimulus-evoked activity at mesopic light levels. Morphological analysis of the retina did not show any significant differences in the gross morphology, such as thickness of retinal layers or cell number in the inner and outer nuclear layer. The cell bodies in the inner nuclear layer, however, were larger in the peripheral retina of Jimpy mutant mice. Antibody labeling against cell type-specific markers showed that the number of rod bipolar and horizontal cells was increased in Jimpy mice. In conclusion, whereas the Jimpy mutation has dramatic effects on the myelination of retinal ganglion cell axons, it has moderate effects on retinal morphology and function.

Hyperpolarization-activated cation current Ih of dentate gyrus granule cells is upregulated in human and rat temporal lobe epilepsy.

The hyperpolarization-activated cation current I(h) is an important regulator of neuronal excitability and may contribute to the properties of the dentate gyrus granule (DGG) cells, which constitute the input site of the canonical hippocampal circuit. Here, we investigated changes in I(h) in DGG cells in human temporal lobe epilepsy (TLE) and the rat pilocarpine model of TLE using the patch-clamp technique. Messenger-RNA (mRNA) expression of I(h)-conducting HCN1, 2 and 4 isoforms was determined using semi-quantitative in-situ hybridization. I(h) density was ∼1.8-fold greater in DGG cells of TLE patients with Ammon's horn sclerosis (AHS) as compared to patients without AHS. The magnitude of somatodendritic I(h) was enhanced also in DGG cells in epileptic rats, most robustly during the latent phase after status epilepticus and prior to the occurrence of spontaneous epileptic seizures. During the chronic phase, I(h) was increased ∼1.7-fold. This increase of I(h) was paralleled by an increase in HCN1 and HCN4 mRNA expression, whereas HCN2 expression was unchanged. Our data demonstrate an epilepsy-associated upregulation of I(h) likely due to increased HCN1 and HCN4 expression, which indicate plasticity of I(h) during epileptogenesis and which may contribute to a compensatory decrease in neuronal excitability of DGG cells.

Depression of release by mGluR8 alters Ca2+ dependence of release machinery.

The ubiquitous presynaptic metabotropic glutamate receptors (mGluRs) are generally believed to primarily inhibit synaptic transmission through blockade of Ca(2+) entry. Here, we analyzed how mGluR8 achieves a nearly complete inhibition of glutamate release at hippocampal synapses. Surprisingly, presynaptic Ca(2+) imaging and miniature excitatory postsynaptic current recordings showed that mGluR8 acts without affecting Ca(2+) entry, diffusion, and buffering. We quantitatively compared the Ca(2+) dependence of the inhibition of release by mGluR8 with the inhibition by ω-conotoxin GVIA. These calculations suggest that the inhibition produced by mGluR8 may be explained by a decrease in the apparent Ca(2+) affinity of the release sensor and, to a smaller extent, by a reduction of the maximal release rate. Upon activation of mGluR8, phasic transmitter release toward the end of a train of action potentials is greater as compared with presynaptic inhibition induced by blocking Ca(2+) entry, which is consistent with the important role of Ca(2+) in accelerating the replenishment of released vesicles. The action of mGluR8 was resistant to blockers of classical G-protein transduction pathways including inhibition of adenylate cyclase and may represent a direct effect on the release machinery. In conclusion, our data identify a mode of presynaptic inhibition which allows mGluR8 to profoundly inhibit vesicle fusion while not diminishing vesicle replenishment and which thereby differentially changes the temporal transmission properties of the inhibited synapse.

Fate of neuron-glia synapses during proliferation and differentiation of NG2 cells.

Progenitor cells expressing proteoglycan NG2 (also known as oligodendrocyte precursor cells or polydendrocytes) are widespread in the grey and white matter of the CNS; they comprise 8-9% of the total cell population in adult white matter, and 2-3% of total cells in adult grey matter. NG2 cells have a complex stellate morphology, with highly branched processes that may extend more than 100 µm around the cell body. NG2 cells express a complex set of voltage-gated channels, AMPA/kainate and/or γ-aminobutyric acid (GABA)(A) receptors, and receive glutamatergic and/or GABAergic synaptic input from neurons. In every region of the brain NG2 cells are found as proliferative cells, and the fraction of actively cycling NG2 cells is quite high in young as well as in adult animals. During development NG2 cells either differentiate into myelinating oligodendrocytes (and possibly also few astrocytes and neurons) or persist in the brain parenchyma as NG2 cells. This review highlights new findings related to the morphological and electrophysiological changes of NG2 cells, and the fate of synaptic input between neurons and NG2 cells during proliferation and differentiation of these cells in the neonatal and adult nervous system of rodents.

The fate of synaptic input to NG2 glial cells: neurons specifically downregulate transmitter release onto differentiating oligodendroglial cells.

NG2-expressing oligodendrocyte precursor cells (OPCs) are ubiquitous and generate oligodendrocytes throughout the young and adult brain. Previous work has shown that virtually every NG2 cell receives synaptic input from many axons, but the meaning of this signaling is not understood. In particular, it is unclear whether neurons specifically synapse onto OPCs or whether OPCs merely trace adjacent neurotransmitter release sites and are not recognized by the presynaptic neuron. Here, we show with whole-cell recordings from distinct developmental stages of oligodendroglial cells in brain slices that synaptic input essentially disappears as soon as OPCs differentiate into premyelinating oligodendrocytes (NG2(-), DM20/PLP(+), O1(+)). Uncaging experiments and tracer loading revealed that premyelinating oligodendrocytes still express a substantial number of AMPA/kainate receptors and many processes, but spontaneous and stimulated synaptic currents are mostly absent. Nevertheless, in a minority of premyelinating cells, electrical stimulation evoked small synaptic currents with an unusual behavior: their amplitude compared well with the quantal amplitude in OPCs but they occurred asynchronously and with the remarkable latency of 40-100 ms, indicating that the presynaptic release machinery has become ineffective. Mature myelinating oligodendrocytes completely lack AMPA/kainate receptors and respond to uncaging and synaptic stimulation with glutamate transporter currents. Our data show that neurons selectively synapse onto only one of several coexisting developmental stages of glial cells and thereby indicate that neurons indeed specifically signal to OPCs and are able to modulate transmitter output by regulating the local release machinery in a manner specific to the developmental stage of the postsynaptic glial cell.

Kainate receptors and signal integration by NG2 glial cells.

It is well established that NG2 cells throughout the young and adult brain consistently detect the release of single vesicles filled with glutamate from nearby axons. The released neurotransmitter glutamate electrically excites NG2 cells via non-NMDA (N-methyl-D-aspartic acid) glutamate receptors but the individual contribution of AMPA and kainate receptors to neuron-NG2 cell signalling, is not well understood. Here we pharmacologically block AMPA-type glutamate receptors and investigate whether hippocampal NG2 cells also express the kainate subtype of glutamate receptors and what may be their contribution to synaptic connectivity. It has been shown previously that vesicular glutamate release does not lead to a detectable activation of kainate receptors on NG2 cells. Here we report that while bath application of 250 nM-1 muM kainate does not have a major effect on NG2 cells it consistently induces a small and persistent depolarising current. This current was not mimicked by ATPA, suggesting that this current is carried by non-GluR5 containing kainate receptors. In addition to this inward current, nanomolar concentrations of kainate also produced a dramatic increase in the frequency of spontaneous GABA-A receptor-mediated synaptic currents (IPSCs) in NG2 cells. This increase in spontaneous IPSC frequency was even more pronounced on application of the GluR5-specific agonist ATPA (approximately 15-fold increase in frequency). In contrast, mono-synaptic stimulated IPSCs recorded in NG2 cells were unaffected by kainate receptor activation. Those and further experiments show that the occurrence of the high frequency of IPSCs is due to action potential firing of hippocampal interneurons caused by activation of GluR5 receptors on the somatodendritic membrane of the interneurons. Our data suggest that hippocampal kainate receptors are not only important for communication between neurons but may also play a dual and subtype-specific role for neuron-glia signalling: Firstly, extra-synaptic non-GluR5 kainate receptors in the membrane of NG2 cells are ideally suited to instruct NG2 cells on the population activity of local excitatory neurons via ambient glutamate. Secondly, based on the known importance of GluR5 receptors on hippocampal interneurons for the generation of network rhythms and based on our finding that these interneurons heavily project onto NG2 cells, it appears that synaptic activation of interneuronal GluR5 receptors triggers signalling to NG2 cells which transmits the phase and frequency of ongoing network oscillations in the developing hippocampus.

Synapses on NG2-expressing progenitors in the brain: multiple functions?

Progenitor cells expressing the proteoglycan NG2 represent approximately 5% of the total cells in the adult brain, and are found both in grey and white matter regions where they give rise to oligodendrocytes. The finding that these cells receive synaptic contacts from excitatory and inhibitory neurons has not only raised major interest in the possible roles of these synapses, but also stimulated further research on the developmental and cellular functions of NG2-expressing (NG2(+)) progenitors themselves in the context of neural circuit physiology. Here we review recent findings on the functional properties of the synapses on NG2(+) cells in grey and white matter regions of the brain. In this review article we make an attempt to integrate current knowledge on the cellular and developmental properties of NG2(+) progenitors with the functional attributes of their synapses, in order to understand the physiological relevance of neuron-NG2(+) progenitor signal transmission. We propose that, although NG2(+) progenitors receive synaptic contact in all brain regions where they are found, their synapses might have different developmental and functional roles, probably reflecting the distinct functions of NG2(+) progenitors in the brain.