Centre for Neuroscience - Research Publications
Now showing items 1-12 of 99
Combined antagonism of glutamate mGlu5 and adenosine A(2A) receptors interact to regulate alcohol-seeking in rats
(CAMBRIDGE UNIV PRESS, 2008-03-01)
Adenosine and glutamate have been implicated as mediators involved in the self-administration of alcohol. In the present study we sought to determine whether adenosine receptors could interact with metabotropic glutamate receptors to regulate operant responding for alcohol and also the integration of the salience of alcohol-paired cues. Alcohol-preferring (iP) rats were trained to self-administer alcohol under operant conditions. The availability of alcohol was paired with an olfactory cue plus a stimulus light. Rats were examined under fixed ratio responding and also following extinction under a cue-induced reinstatement paradigm. Administration of the selective adenosine A2A receptor antagonist, SCH 58261, reduced fixed ratio responding for alcohol in iP rats in a dose-related manner. Furthermore, the combination of a subthreshold dose of SCH 58261 with a subthreshold dose of the mGlu5 receptor antagonist MTEP also reduced alcohol self-administration and increased the latency to the first reinforced response, suggesting a pre-ingestive effect. Moreover, this combination of SCH 58261 and MTEP also prevented the conditioned reinstatement of alcohol-seeking elicited by the re-presentation of cues previously paired with alcohol availability. In contrast, combinations of the selective adenosine A1 receptor antagonist, DPCPX, with either SCH 58261 or MTEP had no effect on alcohol responding. Collectively, these data suggest a functional interaction between adenosine A2A and mGlu5 receptors in relation to alcohol-seeking and the integration of the drug-related cues.
Genes implicated in multiple sclerosis pathogenesis from consilience of genotyping and expression profiles in relapse and remission
BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Although the pathogenesis of MS remains unknown, it is widely regarded as an autoimmune disease mediated by T-lymphocytes directed against myelin proteins and/or other oligodendrocyte epitopes. METHODS: In this study we investigated the gene expression profiles of peripheral blood cells from patients with RRMS during the relapse and the remission phases utilizing gene microarray technology. Dysregulated genes encoded in regions associated with MS susceptibility from genomic screens or previous transcriptomic studies were identified. The proximal promoter region polymorphisms of two genes were tested for association with disease and expression level. RESULTS: Distinct sets of dysregulated genes during the relapse and remission phases were identified including genes involved in apoptosis and inflammation. Three of these dysregulated genes have been previously implicated with MS susceptibility in genomic screens: TGFbeta1, CD58 and DBC1. TGFbeta1 has one common SNP in the proximal promoter: -508 T>C (rs1800469). Genotyping two Australian trio sets (total 620 families) found a trend for over-transmission of the T allele in MS in females (p < 0.13). Upregulation of CD58 and DBC1 in remission is consistent with their putative roles in promoting regulatory T cells and reducing cell proliferation, respectively. A fourth gene, ALOX5, is consistently found over-expressed in MS. Two common genetic variants were confirmed in the ALOX5 putative promoter: -557 T>C (rs12762303) and a 6 bp tandem repeat polymorphism (GGGCGG) between position -147 and -176; but no evidence for transmission distortion found. CONCLUSION: The dysregulation of these genes tags their metabolic pathways for further investigation for potential therapeutic intervention.
Variants of ST8SIA1 Are Associated with Risk of Developing Multiple Sclerosis
(PUBLIC LIBRARY SCIENCE, 2008-07-09)
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system of unknown etiology with both genetic and environmental factors playing a role in susceptibility. To date, the HLA DR15/DQ6 haplotype within the major histocompatibility complex on chromosome 6p, is the strongest genetic risk factor associated with MS susceptibility. Additional alleles of IL7 and IL2 have been identified as risk factors for MS with small effect. Here we present two independent studies supporting an allelic association of MS with polymorphisms in the ST8SIA1 gene, located on chromosome 12p12 and encoding ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1. The initial association was made in a single three-generation family where a single-nucleotide polymorphism (SNP) rs4762896, was segregating together with HLA DR15/DQ6 in MS patients. A study of 274 family trios (affected child and both unaffected parents) from Australia validated the association of ST8SIA1 in individuals with MS, showing transmission disequilibrium of the paternal alleles for three additional SNPs, namely rs704219, rs2041906, and rs1558793, with p = 0.001, p = 0.01 and p = 0.01 respectively. These findings implicate ST8SIA1 as a possible novel susceptibility gene for MS.
Metabotropic glutamate 5 receptors regulate sensitivity to ethanol in mice
(CAMBRIDGE UNIV PRESS, 2008-09-01)
The metabotropic glutamate receptor 5 (mGlu5) has been implicated in ethanol- and drug-seeking behaviours in rodent studies. Here we examine a number of ethanol-related behavioural assays in mice lacking mGlu5 and wild-type littermates. In a two-bottle free-choice paradigm, mGlu5-deficient mice consumed less ethanol with a reduced preference compared to wild-type mice. Indeed, mGlu5-deficienct mice were ethanol-avoiding at both concentrations of ethanol proffered (5% and 10% v/v). However, there was no difference in the rate of hepatic ethanol and acetaldehyde metabolism between genotypes and consumption of saccharin was similar. In a conditioned place preference study, mGlu5-deficient mice displayed a place preference for ethanol when conditioned with a low dose (1g/kg) of ethanol. Thus, while mGlu5-deficient mice consume less ethanol (with a reduced preference) than wild-type mice, this is not apparently related to impaired hepatic metabolism or a lack of reward from ethanol. Rather, we provide evidence that deletion of the mGlu5 receptor increases sensitivity to centrally mediated effects of ethanol.
Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20
(NATURE PUBLISHING GROUP, 2009-07-01)
To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).
Cocaine-mediated synaptic potentiation is absent in VTA neurons from mGlu5-deficient mice
(OXFORD UNIV PRESS, 2010-03-01)
Drugs of abuse have the ability to instantiate plastic adaptations within the central nervous system, and this property may relate to the development and persistence of addiction. In this context, a single exposure to cocaine in rodents may induce synaptic plasticity by increasing the AMPA/NMDA receptor excitatory post-synaptic current (EPSC) amplitude ratio in dopaminergic cells of the ventral tegmental area (VTA). Here, we examine the role of the metabotropic glutamate 5 (mGlu5) receptor in this regard using a genetic mouse model. The control AMPA/NMDA EPSC ratio is reduced in mGlu5-deficient mice compared to wild-types. Moreover, cocaine-induced enhancement of this EPSC ratio is also absent in mutant mice, which suggests that mGlu5 receptors are required for single-dose cocaine-induced plasticity onto VTA cells. While the temporal profile of hyperactivity to acute cocaine is altered in mGlu5-deficient mice; these mice still develop and express sensitized psychomotor responses to cocaine. These data suggest that the mGlu5 receptor is required for cocaine-induced plasticity in VTA dopaminergic cells. In contrast, the mGlu5 receptor may not be essential for psychostimulant behavioural sensitization; although it probably impacts other aspects drug addiction, such as motivation to self-administer.
Informatics and data mining tools and strategies for the human connectome project.
(Frontiers Media SA, 2011)
The Human Connectome Project (HCP) is a major endeavor that will acquire and analyze connectivity data plus other neuroimaging, behavioral, and genetic data from 1,200 healthy adults. It will serve as a key resource for the neuroscience research community, enabling discoveries of how the brain is wired and how it functions in different individuals. To fulfill its potential, the HCP consortium is developing an informatics platform that will handle: (1) storage of primary and processed data, (2) systematic processing and analysis of the data, (3) open-access data-sharing, and (4) mining and exploration of the data. This informatics platform will include two primary components. ConnectomeDB will provide database services for storing and distributing the data, as well as data analysis pipelines. Connectome Workbench will provide visualization and exploration capabilities. The platform will be based on standard data formats and provide an open set of application programming interfaces (APIs) that will facilitate broad utilization of the data and integration of HCP services into a variety of external applications. Primary and processed data generated by the HCP will be openly shared with the scientific community, and the informatics platform will be available under an open source license. This paper describes the HCP informatics platform as currently envisioned and places it into the context of the overall HCP vision and agenda.
TRPM8 and Na(v)1.8 sodium channels are required for transthyretin-induced calcium influx in growth cones of small-diameter TrkA-positive sensory neurons
(BIOMED CENTRAL LTD, 2011-03-04)
BACKGROUND: Familial amyloidotic polyneuropathy (FAP) is a peripheral neuropathy caused by the extracellular accumulation and deposition of insoluble transthyretin (TTR) aggregates. However the molecular mechanism that underlies TTR toxicity in peripheral nerves is unclear. Previous studies have suggested that amyloidogenic proteins can aggregate into oligomers which disrupt intracellular calcium homeostasis by increasing the permeability of the plasma membrane to extracellular calcium. The aim of the present study was to examine the effect of TTR on calcium influx in dorsal root ganglion neurons. RESULTS: Levels of intracellular cytosolic calcium were monitored in dorsal root ganglion (DRG) neurons isolated from embryonic rats using the calcium-sensitive fluorescent indicator Fluo4. An amyloidogenic mutant form of TTR, L55P, induced calcium influx into the growth cones of DRG neurons, whereas wild-type TTR had no significant effect. Atomic force microscopy and dynamic light scattering studies confirmed that the L55P TTR contained oligomeric species of TTR. The effect of L55P TTR was decreased by blockers of voltage-gated calcium channels (VGCC), as well as by blockers of Nav1.8 voltage-gated sodium channels and transient receptor potential M8 (TRPM8) channels. siRNA knockdown of TRPM8 channels using three different TRPM8 siRNAs strongly inhibited calcium influx in DRG growth cones. CONCLUSIONS: These data suggest that activation of TRPM8 channels triggers the activation of Nav1.8 channels which leads to calcium influx through VGCC. We suggest that TTR-induced calcium influx into DRG neurons may contribute to the pathophysiology of FAP. Furthermore, we speculate that similar mechanisms may mediate the toxic effects of other amyloidogenic proteins such as the β-amyloid protein of Alzheimer's disease.
Comparing genotyping algorithms for Illumina's Infinium whole-genome SNP BeadChips
BACKGROUND: Illumina's Infinium SNP BeadChips are extensively used in both small and large-scale genetic studies. A fundamental step in any analysis is the processing of raw allele A and allele B intensities from each SNP into genotype calls (AA, AB, BB). Various algorithms which make use of different statistical models are available for this task. We compare four methods (GenCall, Illuminus, GenoSNP and CRLMM) on data where the true genotypes are known in advance and data from a recently published genome-wide association study. RESULTS: In general, differences in accuracy are relatively small between the methods evaluated, although CRLMM and GenoSNP were found to consistently outperform GenCall. The performance of Illuminus is heavily dependent on sample size, with lower no call rates and improved accuracy as the number of samples available increases. For X chromosome SNPs, methods with sex-dependent models (Illuminus, CRLMM) perform better than methods which ignore gender information (GenCall, GenoSNP). We observe that CRLMM and GenoSNP are more accurate at calling SNPs with low minor allele frequency than GenCall or Illuminus. The sample quality metrics from each of the four methods were found to have a high level of agreement at flagging samples with unusual signal characteristics. CONCLUSIONS: CRLMM, GenoSNP and GenCall can be applied with confidence in studies of any size, as their performance was shown to be invariant to the number of samples available. Illuminus on the other hand requires a larger number of samples to achieve comparable levels of accuracy and its use in smaller studies (50 or fewer individuals) is not recommended.
Gas6 Increases Myelination by Oligodendrocytes and Its Deficiency Delays Recovery following Cuprizone-Induced Demyelination
(PUBLIC LIBRARY SCIENCE, 2011-03-10)
Multiple sclerosis (MS) is a complex demyelinating disease of the central nervous system. Current research has shown that at least in some cases, the primary insult in MS could be directed at the oligodendrocyte, and that the earliest immune responses are primarily via innate immune cells. We have identified a family of receptor protein tyrosine kinases, known as the TAM receptors (Tyro3, Axl and Mertk), as potentially important in regulating both the oligodendrocyte and immune responses. We have previously shown that Gas6, a ligand for the TAM receptors, can affect the severity of demyelination in mice, with a loss of signalling via Gas6 leading to decreased oligodendrocyte survival and increased microglial activation during cuprizone-induced demyelination. We hypothesised TAM receptor signalling would also influence the extent of recovery in mice following demyelination. A significant effect of the absence of Gas6 was detected upon remyelination, with a lower level of myelination after 4 weeks of recovery in comparison with wild-type mice. The delay in remyelination was accompanied by a reduction in oligodendrocyte numbers. To understand the molecular mechanisms that drive the observed effects, we also examined the effect of exogenous Gas6 in in vitro myelination assays. We found that Gas6 significantly increased myelination in a dose-dependent manner, suggesting that TAM receptor signalling could be directly involved in myelination by oligodendrocytes. The reduced rate of remyelination in the absence of Gas6 could thus result from a lack of Gas6 at a critical time during myelin production after injury. These findings establish Gas6 as an important regulator of both CNS demyelination and remyelination.
mGlu5 receptor functional interactions and addiction
(FRONTIERS MEDIA SA, 2012-01-01)
The idea of "receptor mosaics" is that proteins may form complex and dynamic networks with respect to time and composition. These have the potential to markedly expand the diversity and specificity of G protein-coupled receptors (GPCR) signaling, particularly in neural cells, where a few key receptors have been implicated in many neurological and psychiatric disorders, including addiction. Metabotropic glutamate type 5 receptors (mGlu5) can form complexes with other GPCRs, including adenosine A(2A) and dopamine D(2) receptors. mGlu5-containing complexes have been reported in the striatum, a brain region critical for mediating the rewarding and incentive motivational properties of drugs of abuse. mGlu5-containing complexes and/or downstream interactions between divergent receptors may play roles in addiction-relevant behaviors. Interactions between mGlu5 receptors and other GPCRs can regulate the rewarding and conditioned effects of drugs as well as drug-seeking behaviors. mGlu5 complexes may influence striatal function, including GABAergic output of striatopallidal neurons and glutamatergic input from corticostriatal afferents. Given their discrete localization, mGlu5-[non-mGlu5] receptor interactions and/or mGlu5-containing complexes may minimize off-target effects and thus provide a novel avenue for drug discovery. The therapeutic targeting of receptor-receptor functional interactions and/or receptor mosaics in a tissue specific or temporal manner (for example, a sub-population of receptors in a "pathological state") might reduce detrimental side effects that may otherwise impair vital brain functions.