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1.  Physiological Function of Microglia 
Neuron glia biology  2011;7(1):1-3.
Broad interest in the rapidly advancing field of microglial involvement in forming neural circuits is evident from the accumulating findings published in leading journals. This special issue of Neuron Glia Biology contains a special collection of research articles and reviews concerning the new appreciation of microglial function in the normal physiology of the brain that extend beyond their traditionally understood role in pathology.
PMCID: PMC4439926  PMID: 22857736
2.  Glutamate receptors: The cause or cure in perinatal white matter injury? 
Neuron glia biology  2012;6(4):209-211.
Glutamate toxicity from hypoxia-ischemia during the perinatal period causes white matter injury that can result in long-term motor and intellectual disability. Blocking ionotropic glutamate receptors has been shown to inhibit oligodendrocyte injury in vitro, but glutamate receptor antagonists have not yet proven helpful in clinical studies. The opposite approach of activating glutamate receptors on developing oligodendrocytes shows promise in experimental studies on rodents. Group I metabotropic glutamate receptors are expressed transiently on developing oligodendrocytes in humans during the perinatal period, and the blood-brain-barrier permeable agonist of group I mGluRs, ACPD (1-aminocyclopentane-trans-1,3,-dicarboxylic acid), reduces white matter damage significantly in a rat model of perinatal hypoxia-ischemia. The results suggest drugs activating this class of glutamate receptors could provide a new therapeutic approach for preventing cerebral palsy and other neurological consequences of diffuse white matter injury in premature infants.
PMCID: PMC4440225  PMID: 22217580
paraventricular leuckomalacia; cerebral palsy; hypoxia; premature infants; glutamate toxicity; axon-oligodendrocyte signaling; myelination
3.  Involvement of calcitonin gene-related peptide and CCL2 production in CD40-mediated behavioral hypersensitivity in a model of neuropathic pain 
Neuron glia biology  2012;7(0):117-128.
The neuropeptide calcitonin gene-related peptide (CGRP) is known to play a pro-nociceptive role after peripheral nerve injury upon its release from primary afferent neurons in preclinical models of neuropathic pain. We previously demonstrated a critical role for spinal cord microglial CD40 in the development of spinal nerve L5 transection (L5Tx)-induced mechanical hypersensitivity. Herein, we investigated whether CGRP is involved in the CD40-mediated behavioral hypersensitivity. First, L5Tx was found to significantly induce CGRP expression in wild-type (WT) mice up to 14 days post-L5Tx. This increase in CGRP expression was reduced in CD40 knockout (KO) mice at day 14 post-L5Tx. Intrathecal injection of the CGRP antagonist CGRP8–37 significantly blocked L5Tx-induced mechanical hypersensitivity. In vitro, CGRP induced glial IL-6 and CCL2 production, and CD40 stimulation added to the effects of CGRP in neonatal glia. Further, there was decreased CCL2 production in CD40 KO mice compared to WT mice 21 days post-L5Tx. However, CGRP8–37 did not significantly affect spinal cord CCL2 production following L5Tx in WT mice. Altogether, these data suggest that CD40 contributes to the maintenance of behavioral hypersensitivity following peripheral nerve injury in part through two distinct pathways, the enhancement of CGRP expression and spinal cord CCL2 production.
PMCID: PMC4110723  PMID: 22377050
Spinal nerve L5 transection; glia; chemokine; cytokine; CCL2
4.  A dominant connexin43 mutant does not have dominant effects on gap junction coupling in astrocytes 
Neuron glia biology  2011;6(4):10.1017/S1740925X11000019.
Dominant mutations in GJA1, the gene encoding the gap junction protein connexin43 (Cx43), cause oculodentodigital dysplasia (ODDD), a syndrome affecting multiple tissues, including the central nervous system (CNS). We investigated the effects of the G60S mutant, which causes a similar, dominant phenotype in mice (Gja1Jrt/+). Astrocytes in acute brain slices from Gja1Jrt/+ mice transfer sulforhodamine-B comparably to that in their wild-type (WT) littermates. Further, astrocytes and cardiomyocytes cultured from Gja1Jrt/+ mice showed a comparable transfer of lucifer yellow to those from WT mice. In transfected cells, the G60S mutant formed gap junction (GJ) plaques but not functional channels. In co-transfected cells, the G60S mutant co-immunoprecipitated with WT Cx43, but did not diminish GJ coupling as measured by dual patch clamp. Thus, whereas G60S has dominant effects, it did not appreciably reduce GJ coupling.
PMCID: PMC3848784  PMID: 21375791
ODDD; astrocytes; connexin
5.  Myelin sheaths are formed with proteins that originated in vertebrate lineages 
Neuron glia biology  2008;4(2):137-152.
All vertebrate nervous systems, except those of agnathans, make extensive use of the myelinated fiber, a structure formed by coordinated interplay between neuronal axons and glial cells. Myelinated fibers, by enhancing the speed and efficiency of nerve cell communication allowed gnathostomes to evolve extensively, forming a broad range of diverse lifestyles in most habitable environments. The axon-covering myelin sheaths are structurally and biochemically novel as they contain high portions of lipid and a few prominent low molecular weight proteins often considered unique to myelin. Here we searched genome and EST databases to identify orthologs and paralogs of the following myelin-related proteins: (1) myelin basic protein (MBP), (2) myelin protein zero (MPZ, formerly P0), (3) proteolipid protein (PLP1, formerly PLP), (4) peripheral myelin protein-2 (PMP2, formerly P2), (5) peripheral myelin protein-22 (PMP22) and (6) stathmin-1 (STMN1). Although widely distributed in gnathostome/vertebrate genomes, neither MBP nor MPZ are present in any of nine invertebrate genomes examined. PLP1, which replaced MPZ in tetrapod CNS myelin sheaths, includes a novel ‘tetrapod-specific’ exon (see also Möbius et al., 2009). Like PLP1, PMP2 first appears in tetrapods and like PLP1 its origins can be traced to invertebrate paralogs. PMP22, with origins in agnathans, and STMN1 with origins in protostomes, existed well before the evolution of gnathostomes. The coordinated appearance of MBP and MPZ with myelin sheaths and of PLP1 with tetrapod CNS myelin suggests interdependence – new proteins giving rise to novel vertebrate structures.
PMCID: PMC3781599  PMID: 19737434
Myelin basic protein; myelin protein zero; PMP22; PMP2; stathmin
6.  Brain-Derived Neurotrophic Factor from Microglia: A Molecular Substrate for Neuropathic Pain 
Neuron glia biology  2012;7(1):99-108.
One of the most significant advances in pain research is the realization that neurons are not the only cell type involved in the etiology of chronic pain. This realization has caused a radical shift from the previous dogma that neuronal dysfunction alone accounts for pain pathologies, to the current framework of thinking that takes into account all cell types within the central nervous system (CNS). This shift in thinking stems from growing evidence that glia can modulate the function and directly shape the cellular architecture of nociceptive networks in the CNS. Microglia, in particular, are increasingly recognized as active principal players that respond to changes in physiological homeostasis by extending their processes toward the site of neural damage, and by releasing specific factors that have profound consequences on neuronal function and that contribute to CNS pathologies caused by disease or injury. A key molecule that modulates microglia activity is ATP, an endogenous ligand of the P2 receptor family. Microglia express several P2 receptor subtypes, and of these the P2X4 receptor subtype has emerged as a core microglia-neuron signaling pathway: activation of this receptor drives the release of brain-derived neurotrophic factor (BDNF), a cellular substrate that causes disinhibition of pain-transmitting spinal lamina I neurons. Converging evidence points to BDNF from spinal microglia as being a critical microglia-neuron signalling molecule that gates aberrant nociceptive processing in the spinal cord. The present review highlights recent advances in our understanding of P2X4 receptor-mediated signaling and regulation of BDNF in microglia, as well as the implications for microglia-neuron interactions in the pathobiology of neuropathic pain.
PMCID: PMC3748035  PMID: 22613083 CAMSID: cams3159
Microglia; Brain-derived neurotrophic factor; Purinoceptors; Neuropathic pain; Nerve injury; Chronic pain
7.  Synaptic plasticity and Ca2+ signalling in astrocytes 
Neuron glia biology  2010;6(3):141-146.
There is a growing body of evidence suggesting a functional relationship between Ca2+ signals generated in astroglia and the functioning of nearby excitatory synapses. Interference with endogenous Ca2+ homeostasis inside individual astrocytes has been shown to affect synaptic transmission and its use-dependent changes. However, establishing the causal link between source-specific, physiologically relevant intracellular Ca2+ signals, the astrocytic release machinery and the consequent effects on synaptic transmission has proved difficult. Improved methods of Ca2+ monitoring in situ will be essential for resolving the ambiguity in understanding the underlying Ca2+ signalling cascades.
PMCID: PMC3443462  PMID: 20939938
Astrocyte; plasticity; glia; synapse
8.  Monitoring astrocyte calcium microdomains with improved membrane targeted GCaMP reporters 
Neuron glia biology  2010;6(3):183-191.
Astrocytes are involved in synaptic and cerebrovascular regulation in the brain. These functions are regulated by intracellular calcium signalling that is thought to reflect a form of astrocyte excitability. In a recent study, we reported modification of the genetically encoded calcium indicator (GECI) GCaMP2 with a membrane-tethering domain, Lck, to generate Lck-GCaMP2. This GECI allowed us to detect novel microdomain calcium signals. The microdomains were random and ‘spotty’ in nature. In order to detect such signals more reliably, in the present study we further modified Lck-GCaMP2 to carry three mutations in the GCaMP2 moiety (M153K, T203V within EGFP and N60D in the CaM domain) to generate Lck-GCaMP3. We directly compared Lck-GCaMP2 and Lck-GCaMP3 by assessing their ability to monitor several types of astrocyte calcium signals with a focus on spotty microdomains. Our data show that Lck-GCaMP3 is between two- and four-times better than Lck-GCaMP2 in terms of its basal fluorescence intensity, signal-to-noise and its ability to detect microdomains. The use of Lck-GCaMP3 thus represents a significantly improved way to monitor astrocyte calcium signals, including microdomains, and will facilitate detailed exploration of their molecular mechanisms and physiological roles.
PMCID: PMC3136572  PMID: 21205365
Glia; neuron; interactions; signalling
9.  Development of functional units within trigeminal ganglia correlates with increased expression of proteins involved in neuron–glia interactions 
Neuron glia biology  2010;6(3):171-181.
Cell bodies of trigeminal nerves, which are located in the trigeminal ganglion, are completely surrounded by satellite glial cells and together form a functional unit that regulates neuronal excitability. The goals of this study were to investigate the cellular organization of the rat trigeminal ganglia during postnatal development and correlate those findings with expression of proteins implicated in neuron–glia interactions. During postnatal development there was an increase in the volume of the neuronal cell body, which correlated with a steady increase in the number of glial cells associated with an individual neuron from an average of 2.16 at birth to 7.35 on day 56 in young adults. Interestingly, while the levels of the inwardly rectifying K+ channel Kir4.1 were barely detectable during the first week, its expression in satellite glial cells increased by day 9 and correlated with initial formation of functional units. Similarly, expression of the vesicle docking protein SNAP-25 and neuropeptide calcitonin gene-related peptide was readily detected beginning on day 9 and remained elevated throughout postnatal development. Based on our findings, we propose that the expression of proteins involved in facilitating neuron–glia interactions temporally correlates with the formation of mature functional units during postnatal development of trigeminal ganglion.
PMCID: PMC3196797  PMID: 21205366
Kir4.1; CGRP; SNAP-25
10.  Bergmann glial ensheathment of dendritic spines regulates synapse number without affecting spine motility 
Neuron glia biology  2010;6(3):193-200.
In the cerebellum, lamellar Bergmann glial (BG) appendages wrap tightly around almost every Purkinje cell dendritic spine. The function of this glial ensheathment of spines is not entirely understood. The development of ensheathment begins near the onset of synaptogenesis, when motility of both BG processes and dendritic spines are high. By the end of the synaptogenic period, ensheathment is complete and motility of the BG processes decreases, correlating with the decreased motility of dendritic spines. We therefore have hypothesized that ensheathment is intimately involved in capping synaptogenesis, possibly by stabilizing synapses. To test this hypothesis, we misexpressed GluR2 in an adenoviral vector in BG towards the end of the synaptogenic period, rendering the BG α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) Ca2+-impermeable and causing glial sheath retraction. We then measured the resulting spine motility, spine density and synapse number. Although we found that decreasing ensheathment at this time does not alter spine motility, we did find a significant increase in both synaptic pucta and dendritic spine density. These results indicate that consistent spine coverage by BG in the cerebellum is not necessary for stabilization of spine dynamics, but is very important in the regulation of synapse number.
PMCID: PMC3244562  PMID: 21044397
Synaptogenesis; Purkinje cell; cerebellum; GluR2
11.  Can satellite glial cells be therapeutic targets for pain control? 
Neuron glia biology  2010;6(1):63-71.
Satellite glial cells (SGCs) undergo phenotypic changes and divide the following injury into a peripheral nerve. Nerve injury, also elicits an immune response and several antigen-presenting cells are found in close proximity to SGCs. Silencing SCG-specific molecules involved in intercellular transport (Connexin 43) or glutamate recycling (glutamine synthase) can dramatically alter nociceptive responses of normal and nerve-injured rats. Transducing SGCs with glutamic acid decarboxylase can produce analgesia in models of trigeminal pain. Taken together these data suggest that SGCs may play a role in the genesis or maintenance of pain and open a range of new possibilities for curing neuropathic pain.
PMCID: PMC3139431  PMID: 20566001
Nociception; trigeminal; immune cells; GABA; RNAi
12.  Differential expression of connexins in trigeminal ganglion neurons and satellite glial cells in response to chronic or acute joint inflammation 
Neuron glia biology  2009;4(4):295-306.
Trigeminal nerve activation in response to inflammatory stimuli has been shown to increase neuron–glia communication via gap junctions in trigeminal ganglion. The goal of this study was to identify changes in the expression of gap junction proteins, connexins (Cxs), in trigeminal ganglia in response to acute or chronic joint inflammation. Although mRNA for Cxs 26, 36, 40 and 43 was detected under basal conditions, protein expression of only Cxs 26, 36 and 40 increased following capsaicin or complete Freund’s adjuvant (CFA) injection into the temporomandibular joint (TMJ). While Cx26 plaque formation between neurons and satellite glia was transiently increased following capsaicin injections, Cx26 plaque formation between neurons and satellite glia was sustained in response to CFA. Interestingly, levels of Cx36 and Cx40 were only elevated in neurons following capsaicin or CFA injections, but the temporal response was similar to that observed for Cx26. In contrast, Cx43 expression was not increased in neurons or satellite glial cells in response to CFA or capsaicin. Thus, trigeminal ganglion neurons and satellite glia can differentially regulate Cx expression in response to the type and duration of inflammatory stimuli, which likely facilitates increased neuron–glia communication during acute and chronic inflammation and pain in the TMJ.
PMCID: PMC3138122  PMID: 19674505
Capsaicin; complete Freund’s adjuvant; gap junctions; hemichannels; temporomandibular joint disorders
13.  Neuronal soma-satellite glial cell interactions in sensory ganglia and the participation of purinergic receptors 
Neuron glia biology  2010;6(1):53-62.
It has been known for some time that the somata of neurons in sensory ganglia respond to electrical or chemical stimulation and release transmitters in a Ca2+-dependent manner. The function of the somatic release has not been well delineated. A unique characteristic of the ganglia is that each neuronal soma is tightly enwrapped by satellite glial cells (SGCs). The somatic membrane of a sensory neuron rarely makes synaptic contact with another neuron. As a result, the influence of somatic release on the activity of adjacent neurons is likely to be indirect and/or slow. Recent studies of neuron-SGC interactions have demonstrated that ATP released from the somata of dorsal root ganglion neurons activates SGCs. They in turn exert complex excitatory and inhibitory modulation of neuronal activity. Thus, SGCs are actively involved in the processing of afferent information. In this review, we summarize our understanding of bidirectional communication between neuronal somata and SGCs in sensory ganglia and its possible role in afferent signaling under normal and injurious conditions. The participation of purinergic receptors is emphasized because of their dominant roles in the communication.
PMCID: PMC3120217  PMID: 20604979
somatic ATP release; P2X7 receptor; cytokine release; dorsal root ganglia; pathological nociception
14.  Central Role of Glia in Disease Research 
Neuron glia biology  2010;6(2):91-92.
PMCID: PMC3065246  PMID: 20959032
15.  Uncoupling of astrogliosis from epileptogenesis in adenosine kinase (ADK) transgenic mice 
Neuron glia biology  2009;4(2):91-99.
The astrocytic enzyme adenosine kinase (ADK) is a key negative regulator of the brain’s endogenous anticonvulsant adenosine. Astrogliosis with concomitant upregulation of ADK is part of the epileptogenic cascade and contributes to seizure generation. To molecularly dissect the respective roles of astrogliosis and ADK-expression for seizure generation, we used a transgenic approach to uncouple ADK-expression from astrogliosis: in Adk-tg mice the endogenous Adk-gene was deleted and replaced by a ubiquitously expressed Adk-transgene with novel ectopic expression in pyramidal neurons, resulting in spontaneous seizures. Here, we followed a unique approach to selectively injure the CA3 of these Adk-tg mice. Using this strategy, we had the opportunity to study astrogliosis and epileptogenesis in the absence of the endogenous astrocytic Adk-gene. After triggering epileptogenesis we demonstrate astrogliosis without upregulation of ADK, but lack of seizures, whereas matching wild-type animals developed astrogliosis with upregulation of ADK and spontaneous recurrent seizures. By uncoupling ADK-expression from astrogliosis, we demonstrate that global expression levels of ADK rather than astrogliosis per se contribute to seizure generation.
PMCID: PMC3045053  PMID: 19674507
astrogliosis; seizures; kainic acid; epileptogenesis; CA3
16.  Glial imaging during synapse remodeling at the neuromuscular junction 
Neuron glia biology  2009;4(4):319-326.
Glia are an indispensable structural and functional component of the synapse. They modulate synaptic transmission and also play important roles in synapse formation and maintenance. The vertebrate neuromuscular junction (NMJ) is a classic model synapse. Due to its large size, simplicity and accessibility, the NMJ has contributed greatly to our understanding of synapse development and organization. In the past decade, the NMJ has also emerged as an effective model for studying glia–synapse interactions, in part due to the development of various labeling techniques that permit NMJs and associated Schwann cells (the glia at NMJs) to be visualized in vitro and in vivo. These approaches have demonstrated that Schwann cells are actively involved in synapse remodeling both during early development and in post-injury reinnervation. In vivo imaging has also recently been combined with serial section transmission electron microscopic (ssTEM) reconstruction to directly examine the ultrastructural organization of remodeling NMJs. In this review, we focus on the anatomical studies of Schwann cell dynamics and their roles in formation, maturation and remodeling of vertebrate NMJs using the highest temporal and spatial resolution methods currently available.
PMCID: PMC2842907  PMID: 19939298
Schwann cell; synapse elimination; reinnervation; in vivo imaging; ssTEM reconstruction
17.  A Model of Tight Junction Function In CNS Myelinated Axons 
Neuron glia biology  2008;4(4):307-317.
The insulative properties of myelin sheaths in the central and peripheral nervous systems (CNS and PNS) are widely thought to derive from the high resistance and low capacitance of the constituent membranes. Although this view adequately accounts for myelin function in large diameter PNS fibers, it poorly reflects the behavior of small fibers that are prominent in many regions of the CNS. Herein, we develop a computational model to more accurately represent conduction in small fibers. By incorporating structural features that, hitherto, have not been simulated, we demonstrate that myelin tight junctions improve saltatory conduction by reducing current flow through the myelin, limiting axonal membrane depolarization and restraining the activation of ion channels beneath the myelin sheath. Accordingly, our simulations provide a novel view of myelin by which tight junctions minimize charging of the membrane capacitance and lower the membrane time constant to improve the speed and accuracy of transmission in small diameter fibers. This study establishes possible mechanisms whereby TJs affect conduction in the absence of overt perturbations to myelin architecture and may in part explain the tremor and gait abnormalities observed in Claudin 11-null mice.
PMCID: PMC2957896  PMID: 20102674
axoglial junctions; claudin; intercellular junctions; knockout; modeling; occluding; paranodal; permeability barrier; radial component; schizophrenia; multiple sclerosis; simulation; myelination; action potential
18.  Bidirectional calcium signaling between satellite glial cells and neurons in cultured mouse trigeminal ganglia 
Neuron glia biology  2009;6(1):43-51.
Astrocytes communicate with neurons, endothelial and other glial cells through transmission of intercellular calcium signals. Satellite glial cells (SGCs) in sensory ganglia share several properties with astrocytes, but whether this type of communication occurs between SGCs and sensory neurons has not been explored. In the present work we used cultured neurons and SGCs from mouse trigeminal ganglia to address this question. Focal electrical or mechanical stimulation of single neurons in trigeminal ganglion cultures increased intracellular calcium concentration in these cells and triggered calcium elevations in adjacent glial cells. Similar to neurons, SGCs responded to mechanical stimulation with increase in cytosolic calcium that spread to the adjacent neuron and neighboring glial cells. Calcium signaling from SGCs to neurons and among SGCs was diminished in the presence of the broad-spectrum P2 receptor antagonist suramin (50 µM) or in the presence of the gap junction blocker carbenoxolone (100 µM), whereas signaling from neurons to SGCs was reduced by suramin, but not by carbenoxolone. Following induction of submandibular inflammation by Complete Freund’s Adjuvant injection, the amplitude of signaling among SGCs and from SGCs to neuron was increased, whereas the amplitude from neuron to SGCs was reduced. These results indicate for the first time the presence of bidirectional calcium signaling between neurons and SGCs in sensory ganglia cultures, which is mediated by the activation of purinergic P2 receptors, and to some extent by gap junctions. Furthermore, the results indicate that not only sensory neurons, but also SGCs release ATP. This form of intercellular calcium signaling likely plays key roles in the modulation of neuronal activity within sensory ganglia in normal and pathological states.
PMCID: PMC2897940  PMID: 19891813
Gap junctions; neuron–glial communication; orofacial hypersensitivity; purinergic receptors
19.  nkx2.2a promotes specification and differentiation of a myelinating subset of oligodendrocyte lineage cells in zebrafish 
Neuron glia biology  2008;4(2):71.
During development, multipotent neural precursors give rise to oligodendrocyte progenitor cells (OPCs), which migrate and divide to produce additional OPCs. Near the end of embryogenesis and during postnatal stages, many OPCs stop dividing and differentiate as myelinating oligodendrocytes, whereas others persist as nonmyelinating cells. Investigations of oligodendrocyte development in mice indicated that the Nkx2.2 transcription factor both limits the number of OPCs that are formed and subsequently promotes their differentiation, raising the possibility that Nkx2.2 plays a key role in determining myelinating versus nonmyelinating fate. We used in vivo time-lapse imaging and loss-of-function experiments in zebrafish to further explore formation and differentiation of oligodendrocyte lineage cells. Our data show that newly specified OPCs are heterogeneous with respect to gene expression and fate. Whereas some OPCs express the nkx2.2a gene and differentiate as oligodendrocytes, others that do not express nkx2.2a mostly remain as nonmyelinating OPCs. Similarly to mouse, loss of nkx2.2a function results in excess OPCs and delayed oligodendrocyte differentiation. Notably, excess OPCs are formed as a consequence of prolonged OPC production from neural precursor cells. We conclude that Nkx2.2 promotes timely specification and differentiation of myelinating oligodendrocyte lineage cells from species representing different vertebrate taxa.
PMCID: PMC2821284  PMID: 19737431
Olig2; zebrafish; neural precursors; glia
20.  Bipolar disorder: involvement of signaling cascades and AMPA receptor trafficking at synapses 
Neuron glia biology  2004;1(3):231-243.
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.
PMCID: PMC2763507  PMID: 18634600
Lithium; valproate; antidepressant; bipolar disorder; glutamatergic system
21.  Activity-dependent neuron–glial signaling by ATP and leukemia-inhibitory factor promotes hippocampal glial cell development⋆ 
Neuron glia biology  2008;4(1):43-55.
Activity-dependent signaling between neurons and astrocytes contributes to experience-dependent plasticity and development of the nervous system. However, mechanisms responsible for neuron–glial interactions and the releasable factors that underlie these processes are not well understood. The pro-inflammatory cytokine, leukemia-inhibitory factor (LIF), is transiently expressed postnatally by glial cells in the hippocampus and rapidly up-regulated by enhanced neural activity following seizures. To test the hypothesis that spontaneous neural activity regulates glial development in hippocampus via LIF signaling, we blocked spontaneous activity with the sodium channel blocker tetrodotoxin (TTX) in mixed hippocampal cell cultures in combination with blockers of LIF and purinergic signaling. TTX decreased the number of GFAP-expressing astrocytes in hippocampal cell culture. Furthermore, blocking purinergic signaling by P2Y receptors contributed to reduced numbers of astrocytes. Blocking activity or purinergic signaling in the presence of function-blocking antibodies to LIF did not further decrease the number of astrocytes. Moreover, hippocampal cell cultures prepared from LIF −/− mice had reduced numbers of astrocytes and activity-dependent neuron–glial signaling promoting differentiation of astrocytes was absent. The results show that endogenous LIF is required for normal development of hippocampal astrocytes, and this process is regulated by spontaneous neural impulse activity through the release of ATP.
PMCID: PMC2756042  PMID: 19267953
Activity dependent; cytokine; glial differentiation; neuron–glia signaling; synaptic plasticity
22.  Reduced EGFR signaling in adult progenitors of the subventricular zone attenuates oligodendrogenesis after demyelination 
Neuron glia biology  2007;3(3):209-220.
Neural progenitor cells expressing the NG2 proteoglycan are found in different regions of the adult mammalian brain, where they display distinct morphologies and proliferative rates. In the developing postnatal and adult mouse, NG2+ cells represent a major cell population of the subventricular zone (SVZ). NG2+ cells divide in the anterior and lateral region of the SVZ, and are stimulated to proliferate and migrate out of the SVZ by focal demyelination of the corpus callosum (CC). Many NG2+ cells are labeled by GFP-retrovirus injection into the adult SVZ, demonstrating that NG2+ cells actively proliferate under physiological conditions and after demyelination. In the wa2 mouse, which is characterized by reduced EGFR signaling, NG2+ cell proliferation, under normal physiological conditions and after focal demyelination, is significantly attenuated. This results in reduced SVZ-to-lesion migration of NG2+ cells and oligodendrogenesis in the lesion. Expression of VEGF and EGFR ligands, such as HB-EGF and TGF-alpha, is upregulated in the SVZ after focal demyelination of the CC. EGF-induced oligodendrogenesis and myelin protein expression in cultured wild-type SVZ cells were significantly attenuated in wa2 SVZ cells. Our results demonstrate that the NG2+ cell response in the SVZ and their subsequent differentiation in CC after focal demyelination are dependent upon EGFR signaling.
PMCID: PMC2696258  PMID: 18634612
NG2 progenitors; cell proliferation; cell migration; myelin; growth factors
23.  Events at the transition between cell cycle exit and oligodendrocyte progenitor differentiation: the role of HDAC and YY1 
Neuron glia biology  2007;3(3):221-231.
The complexity of the adult brain is the result of an integrated series of developmental events that depends on appropriate timing of differentiation. The importance of transcriptional regulatory networks and epigenetic mechanisms of regulation of gene expression is becoming increasingly evident. Among these mechanisms, previous work has revealed the importance of histone deacetylation in oligodendrocyte differentiation. In this manuscript we define the region of interaction between transcription factor Yin-Yang 1 (YY1) and histone deacetylase 1, and characterize the functional consequences of YY1 overexpression on the differentiation of oligodendrocyte progenitors.
PMCID: PMC2656678  PMID: 18634613
chromatin; transcription; development; brain; myelin; epigenetic
24.  Interactions of Sox10 and Egr2 in Myelin Gene Regulation 
Neuron glia biology  2007;3(4):377-387.
Myelination in the PNS is accompanied by a large induction of the Myelin Protein Zero (Mpz) gene to produce the most abundant component in peripheral myelin. Analyses of knockout mice have shown that the EGR2/Krox20 and SOX10 transcription factors are required for Mpz expression. Our recent work has shown that the dominant EGR2 mutations associated with human peripheral neuropathies cause disruption of EGR2/SOX10 synergy at specific sites, including a conserved enhancer element in the first intron of the Mpz gene. Further investigation of Egr2/Sox10 interactions reveals that activation of the Mpz intron element by Egr2 requires both Sox10-binding sites. In addition, both Egr1 and Egr3 cooperate with Sox10 to activate this element, which indicates that this capacity is conserved among Egr family members. Finally, a conserved composite structure of Egr2/Sox10-binding sites in the genes encoding Mpz, Myelin-associated glycoprotein (Mag), and Myelin Basic Protein (Mbp) genes was used to screen for similar modules in other myelin genes, revealing a potential regulatory element in the periaxin gene. Overall, these results elucidate a working model for developmental regulation of Mpz expression, several facets of which extend to regulation of other peripheral myelin genes.
PMCID: PMC2605513  PMID: 18634568
Charcot; Krox20; transcription; myelin; Schwann cells
25.  Connexin and pannexin mediated cell—cell communication 
Neuron glia biology  2007;3(3):199-208.
In this review, we briefly summarize what is known about the properties of the three families of gap junction proteins, connexins, innexins and pannexins, emphasizing their importance as intercellular channels that provide ionic and metabolic coupling and as non-junctional channels that can function as a paracrine signaling pathway. We discuss that two distinct groups of proteins form gap junctions in deuterostomes (connexins) and protostomes (innexins), and that channels formed of the deuterostome homologues of innexins (pannexins) differ from connexin channels in terms of important structural features and activation properties. These differences indicate that the two families of gap junction proteins serve distinct, complementary functions in deuterostomes. In several tissues, including the CNS, both connexins and pannexins are involved in intercellular communication, but have different roles. Connexins mainly contribute by forming the intercellular gap junction channels, which provide for junctional coupling and define the communication compartments in the CNS. We also provide new data supporting the concept that pannexins form the non-junctional channels that play paracrine roles by releasing ATP and, thus, modulating the range of the intercellular Ca2+-wave transmission between astrocytes in culture.
PMCID: PMC2588549  PMID: 18634611
Hemichannels; gap junctions; Ca2+ waves; glia; astrocytes; purinergic receptors

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