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1.  Epstein-Barr virus-induced gene 3 negatively regulates neuroinflammation and T cell activation following coronavirus-induced encephalomyelitis 
Journal of neuroimmunology  2012;254(1-2):110-116.
Epstein-Barr virus-induced gene 3 (EBI3) associates with p28 and p35 to form the immunomodulatory cytokines IL-27 and IL-35, respectively. Infection of EBI3−/− mice with the neuroadapted JHM strain of mouse hepatitis virus (JHMV) resulted in increased mortality that was not associated with impaired ability to control viral replication but enhanced T cell and macrophage infiltration into the CNS. IFN-γ secretion from virus-specific CD4+ and CD8+ T cells isolated from infected EBI3−/− mice was augmented while IL-10 expression muted in comparison to infected WT mice. These data demonstrate a regulatory role for EBI3-associated cytokines in controlling host responses following CNS viral infection.
doi:10.1016/j.jneuroim.2012.10.005
PMCID: PMC3534940  PMID: 23102608
2.  Dopamine D2 Antagonist-Induced Striatal Nur77 Expression Requires Activation of mGlu5 Receptors by Cortical Afferents 
Dopamine D2 receptor antagonists modulate gene transcription in the striatum. However, the molecular mechanism underlying this effect remains elusive. Here we used the expression of Nur77, a transcription factor of the orphan nuclear receptor family, as readout to explore the role of dopamine, glutamate, and adenosine receptors in the effect of a dopamine D2 antagonist in the striatum. First, we investigated D2 antagonist-induced Nur77 mRNA in D2L receptor knockout mice. Surprisingly, deletion of the D2L receptor isoform did not reduce eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Next, we tested if an ibotenic acid-induced cortical lesion could block the effect of eticlopride on Nur77 expression. Cortical lesions strongly reduced eticlopride-induced striatal upregulation of Nur77 mRNA. Then, we investigated if glutamatergic neurotransmission could modulate eticlopride-induced Nur77 expression. A combination of a metabotropic glutamate type 5 (mGlu5) and adenosine A2A receptor antagonists abolished eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Direct modulation of Nur77 expression by striatal glutamate and adenosine receptors was confirmed using corticostriatal organotypic cultures. Taken together, these results indicate that blockade of postsynaptic D2 receptors is not sufficient to trigger striatal transcriptional activity and that interaction with corticostriatal presynaptic D2 receptors and subsequent activation of postsynaptic glutamate and adenosine receptors in the striatum is required. Thus, these results uncover an unappreciated role of presynaptic D2 heteroreceptors and support a prominent role of glutamate in the effect of D2 antagonists.
doi:10.3389/fphar.2012.00153
PMCID: PMC3418524  PMID: 22912617
antipsychotic drugs; neuroleptics; Nr4a1; transcription factor; organotypic culture; glutamate receptors; adenosine receptors; striatum
3.  Cell replacement therapies to promote remyelination in a viral model of demyelination 
Journal of neuroimmunology  2010;224(1-2):101-107.
Persistent infection of the central nervous system (CNS) of mice with the neuroadapted JHM strain of mouse hepatitis (MHV) is characterized by ongoing demyelination mediated by inflammatory T cells and macrophages that is similar both clinically and histologically with the human demyelinating disease multiple sclerosis (MS).
Although extensive demyelination occurs in mice persistently-infected with MHV there is only limited remyelination. Therefore, the MHV model of demyelination is a relevant model for studying disease and evaluating therapeutic approaches to protect cells of the oligodendrocyte lineage and promote remyelination. This concept is further highlighted as the etiology of MS remains enigmatic, but viruses have long been considered as potential triggering agents in initiating and/or maintaining MS symptoms. As such, understanding mechanisms associated with promoting repair within the CNS in the context of a persistent viral infection is critical given the possible viral eitiology of MS. This review focuses on recent studies using either mouse neural stem cells (NSCs) or human oligodendrocyte progenitor cells (OPCs) derived from human embryonic stem cell (hESCs) to promote remyelination in mice persistently infected with MHV. In addition, the potential role for chemokines in positional migration of transplanted cells is addressed.
doi:10.1016/j.jneuroim.2010.05.013
PMCID: PMC2919340  PMID: 20627412
4.  Oligodendrocytes as Regulators of Neuronal Networks during Early Postnatal Development 
PLoS ONE  2011;6(5):e19849.
Oligodendrocytes are the glial cells responsible for myelin formation. Myelination occurs during the first postnatal weeks and, in rodents, is completed during the third week after birth. Myelin ensures the fast conduction of the nerve impulse; in the adult, myelin proteins have an inhibitory role on axon growth and regeneration after injury. During brain development, oligodendrocytes precursors originating in multiple locations along the antero-posterior axis actively proliferate and migrate to colonize the whole brain. Whether the initial interactions between oligodendrocytes and neurons might play a functional role before the onset of myelination is still not completely elucidated. In this article, we addressed this question by transgenically targeted ablation of proliferating oligodendrocytes during cerebellum development. Interestingly, we show that depletion of oligodendrocytes at postnatal day 1 (P1) profoundly affects the establishment of cerebellar circuitries. We observed an impressive deregulation in the expression of molecules involved in axon growth, guidance and synaptic plasticity. These effects were accompanied by an outstanding increase of neurofilament staining observed 4 hours after the beginning of the ablation protocol, likely dependent from sprouting of cerebellar fibers. Oligodendrocyte ablation modifies localization and function of ionotropic glutamate receptors in Purkinje neurons. These results show a novel oligodendrocyte function expressed during early postnatal brain development, where these cells participate in the formation of cerebellar circuitries, and influence its development.
doi:10.1371/journal.pone.0019849
PMCID: PMC3093406  PMID: 21589880
5.  CXCR2 Signaling Protects Oligodendrocytes and Restricts Demyelination in a Mouse Model of Viral-Induced Demyelination 
PLoS ONE  2010;5(6):e11340.
Background
The functional role of ELR-positive CXC chemokines during viral – induced demyelination was assessed. Inoculation of the neuroattenuated JHM strain of mouse hepatitis virus (JHMV) into the CNS of susceptible mice results in an acute encephalomyelitis that evolves into a chronic demyelinating disease, modeling white matter pathology observed in the human demyelinating disease Multiple Sclerosis.
Methodology/Principal Findings
JHMV infection induced the rapid and sustained expression of transcripts specific for the ELR (+) chemokine ligands CXCL1 and CXCL2, as well as their binding receptor CXCR2, which was enriched within the spinal cord during chronic infection. Inhibiting CXCR2 signaling with neutralizing antiserum significantly (p<0.03) delayed clinical recovery. Moreover, CXCR2 neutralization was associated with an increase in the severity of demyelination that was independent of viral recrudescence or modulation of neuroinflammation. Rather, blocking CXCR2 was associated with increased numbers of apoptotic cells primarily within white matter tracts, suggesting that oligodendrocytes were affected. JHMV infection of enriched oligodendrocyte progenitor cell (OPC) cultures revealed that apoptosis was associated with elevated expression of cleaved caspase 3 and muted Bcl-2 expression. Inclusion of CXCL1 within JHMV infected cultures restricted caspase 3 cleavage and increased Bcl-2 expression that was associated with a significant (p<0.001) decrease in apoptosis. CXCR2 deficient oligodendrocytes were refractory to CXCL1 mediated protection from JHMV – induced apoptosis, readily activating caspase 3 and down regulating Bcl-2.
Conclusion/Significance
These findings highlight a previously unappreciated role for CXCR2 signaling in protecting oligodendrocyte lineage cells from apoptosis during inflammatory demyelination initiated by viral infection of the CNS.
doi:10.1371/journal.pone.0011340
PMCID: PMC2893165  PMID: 20596532
6.  Genetically determined interaction between the dopamine transporter and the D2 receptor on prefronto-striatal activity and volume in humans 
Dopamine modulation of neuronal activity during memory tasks identifies a non-linear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D2 receptors (encoded by DRD2) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover, in vitro studies have demonstrated that DAT and D2 proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between a DRD2 polymorphism (rs1076560) causing reduced presynaptic D2 receptor expression and the DAT 3’-VNTR variant (affecting DAT expression) in a large sample of healthy subjects undergoing BOLD - fMRI during memory tasks and structural MRI. Results indicated a significant DRD2/DAT interaction in prefrontal cortex and striatum BOLD activity during both working memory and encoding of recognition memory. The differential effect on BOLD activity of the DAT variant was mostly manifest in the context of the DRD2 allele associated with lower presynaptic expression. Similar results were also evident for gray matter volume in caudate. These interactions describe a non-linear relationship between compound genotypes and brain activity or gray matter volume. Complementary data from striatal protein extracts from wild-type and D2 knock-out animals (D2R−/−) indicate that DAT and D2 proteins interact in vivo. Taken together, our results demonstrate that the interaction between genetic variants in DRD2 and DAT critically modulates the non-linear relationship between dopamine and neuronal activity during memory processing.
doi:10.1523/JNEUROSCI.4858-08.2009
PMCID: PMC2686116  PMID: 19176830
working memory; Recognition Memory; FMRI; Dopamine; Transport; D2; Receptor

Results 1-6 (6)