Florey Department of Neuroscience and Mental Health - Research Publications
Permanent URI for this collection
Search Results
Now showing
1 - 2 of 2
-
ItemNo Preview AvailableEvaluating retinal biomarkers in a mouse model of Parkinson's diseaseNguyen, CTO ; Tran, K ; Lim, JKH ; Wong, VHY ; Shahandeh, A ; Vingrys, AJ ; Bui, BV ; Finkelstein, D (Association for Research in Vision and Ophthalmology, 2019-07-01)Purpose : The retina, an accessible outpouching of the central nervous system, may manifest cortical changes that occur with Parkinson’s disease (PD), lending itself as a potential biomarker. PD is characterised by reduced dopamine levels, a neurotransmitter found in amacrine cells. Human PD patients have also shown structural changes in the outer retina. This work aims to determine if retinal function and structure are altered in a murine model of PD and whether deficits can be ameliorated with L-DOPA treatment. Methods : A PD model was induced in adult C57BL6/J mice using MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 4x i.p. injections, 20mg/kg) and vehicle control and examined at day 21 and 45. Another MPTP group was administered L-DOPA (L-3,4-dihydroxyphenylalanine 0.2 mg/ml) or control in their drinking water and assessed at day 45 (n=12–15/group). In ketamine:xylazine anaesthetised (80:10mg/kg) mice full-field dark- and light-adapted electroretinography (ERG) was assessed to target dopamine-related responses. Optical coherence tomography (OCT) was used to quantify thickness of retinal layers. Retinal and cortical tissue were collected for immunohistochemical assessment of changes in tyrosine hydroxylase (TH)and imaged using confocal microscopy. Data (mean±SEM) were compared using unpaired ANOVA and t-tests as appropriate. Results : At day 21 no retinal changes were found. At day 45 dark and light adapted ERGs showed slower amacrine cell responses (oscillatory potential, p<0.05), a finding which reversed with L-DOPA treatment (p<0.05). Other components of the ERG were unchanged. TH staining showed a trend towards decreased retinal levels in MPTP mice but this did not reach significance (p=0.10). Reduced levels of TH were found in the ventral hippocampus of MPTP mice compared with control (p<0.05). OCT revealed thinning of the outer plexiform layer at day 45, and the L-DOPA group exhibited a thinning of the outer nuclear layer (p<0.05). Conclusions : This study shows for the first time that the MPTP model recapitulates key dopaminergic changes previously reported in humans. In particular, electroretinographic changes that correspond with dopaminergic retinal cells occur in the Parkinson’s model and reverse with therapeutic treatment. Structural thinning of the outer retinal layers also occur, which parallels some human findings. This work paves the way for retinal measures as preclinical screening tools in drug development.
-
ItemNo Preview AvailableMETHYLOME-WIDE ASSOCIATION STUDIES FOR MAJOR DEPRESSIVE DISORDER IN BLOOD OVERLAP WITH METHYLATION RESULTS FROM BRAIN AND LARGE-SCALE GWASAberg, K ; Dean, B ; Shabalin, A ; Zhao, M ; Chan, R ; Hattab, M ; van Grootheest, G ; Han, L ; Aghajani, M ; Milaneschi, Y ; Jansen, R ; Xie, L ; Clark, S ; Penninx, B ; van den Oord, E (ELSEVIER SCIENCE BV, 2019-01-01)Background: Epigenetic modifications such as DNA methy- lation provide stability and diversity to the cellular phenotype and aberrant methylation has been implicated in processes underlying psychiatric disorders. Therefore, studies combining DNA methylation and genotype information provide a promis- ing approach to study disorders where genotype information alone has failed to reveal the full etiology. Methods: We applied an optimized MBD-seq protocol to assay the complete CpG methylome in cases with Major Depressive Disorder (MDD) and controls using blood samples (N=1,132) from Netherlands Study of Depression and Anxiety and brain samples (N=64) from the Victorian Brain Bank Network. Data were analyzed with RaMWAS, a novel Biocon- ductor package specifically designed for Methylome-Wide Association Studies (MWAS). To study the overlap between top MWAS findings in blood and brain, we used a permutation based enrichment test (shiftR) that accounted for the depen- dency between adjacent CpG sites. Furthermore, we utilized the methylation data in combination with existing genotype information from the same individuals in a MWAS of CpGs created or destroyed by SNPs. Next, we tested whether top results from this CpG-SNP MWAS overlapped with recent large- scale GWAS to identify robust associations with genomic loci of importance for MDD etiology Results: The MWAS in blood identified five methylome- wide significant sites (P o 5 10-8) from three distinct loci and 472 nominally significant (P o 1 10-5) CpG sites. To study the robustness of the overall MWAS signal, we used an “in-sample” replication based on k-fold cross validation. Results showed that the findings replicated (P = 4.0 10- 10). When we compared blood and brain we found that top blood MWAS findings were significantly enriched for top CpGs in the brain MWAS (P = 5.4 10-3). The MWAS of CpG-SNPs identified 32 nominally significant sites and in- sample replication showed that the signal replicated (P = 2.2 10-8). Finally, the top CpG-SNP MWAS showed a consistent trend towards enrichment in all tested large- scale GWAS, with the most significant enrichment observed for the 23andMe study (P = 4.9 10-3). This overlap involved 55 genes that were overrepresented (P o 0.01) in 12 level-5 gene ontology terms, of which a major portion was related to neuronal regulation, function and development. Discussion: This work involves the largest MWAS for MDD performed to date. Our integrated analysis with brain tissue, genotype information and GWAS results highlighted biological functions of potential value for MDD etiology. Part of the associated methylation marks in blood overlapped with MWAS finding in brain. As blood can easily be collected in a clinical setting, these loci may be of direct value as potential diagnostic biomarkers for MDD.