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- Planert, Henrike, et al.
(author)
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Dynamics of Synaptic Transmission between Fast-Spiking Interneurons and Striatal Projection Neurons of the Direct and Indirect Pathways
- 2010
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In: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 30:9, s. 3499-3507
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Journal article (peer-reviewed)abstract
- The intrastriatal microcircuit is a predominantly inhibitory GABAergic network comprised of a majority of projection neurons [medium spiny neurons (MSNs)] and a minority of interneurons. The connectivity within this microcircuit is divided into two main categories: lateral connectivity between MSNs, and inhibition mediated by interneurons, in particular fast spiking (FS) cells. To understand the operation of striatum, it is essential to have a good description of the dynamic properties of these respective pathways and how they affect different types of striatal projection neurons. We recorded from neuronal pairs, triplets, and quadruplets in slices of rat and mouse striatum and analyzed the dynamics of synaptic transmission between MSNs and FS cells. Retrograde fluorescent labeling and transgenic EGFP (enhanced green fluorescent protein) mice were used to distinguish between MSNs of the direct (striatonigral) and indirect (striatopallidal) pathways. Presynaptic neurons were stimulated with trains of action potentials, and activity-dependent depression and facilitation of synaptic efficacy was recorded from postsynaptic neurons. We found that FS cells provide a strong and homogeneously depressing inhibition of both striatonigral and striatopallidal MSN types. Moreover, individual FS cells are connected to MSNs of both types. In contrast, both MSN types receive sparse and variable, depressing and facilitating synaptic transmission from nearby MSNs. The connection probability was higher for pairs with presynaptic striatopallidal MSNs; however, the variability in synaptic dynamics did not depend on the types of interconnected MSNs. The differences between the two inhibitory pathways were clear in both species and at different developmental stages. Our findings show that the two intrastriatal inhibitory pathways have fundamentally different dynamic properties that are, however, similarly applied to both direct and indirect striatal projections.
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| 2. |
- Öberg Sysojev, Anton, et al.
(author)
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Genome-wide investigation of persistence with methotrexate treatment in early rheumatoid arthritis
- 2024
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In: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332. ; 63:5, s. 1221-1229
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Journal article (peer-reviewed)abstract
- Objectives: To investigate the influence of genetic factors on persistence to treatment of early rheumatoid arthritis (RA) with methotrexate (MTX) monotherapy.Methods: We conducted a genome-wide association study (GWAS) in a sample of 3902 Swedish early RA patients initiating MTX in DMARD-monotherapy as their first ever DMARD. The outcome, short- and long-term persistence to this treatment, was defined as remaining on MTX at one and at three years, respectively, with no additional DMARDs added. As genetic predictors, we investigated individual SNPs, and a polygenic risk score (PRS) based on SNPs associated with RA risk. The SNP-based heritability of persistence was estimated overall and by RA serostatus.Results: No individual SNP reached genome-wide significance (p < 5e-8), neither for persistence at one nor at three years. The RA PRS was not significantly associated with persistence at one (RR = 0.98 (0.96-1.01)) nor three years (RR = 0.96 (0.93-1.00)). The heritability for persistence was estimated to be 0.45 (0.15-0.75) at one year and 0.14 (0-0.40) at three years. Results in seropositive RA were comparable to those in the analysis of RA overall, while heritability estimates and PRS RRs were attenuated towards the null in seronegative RA.Conclusions: Despite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The modest heritability observed, coupled with the broad spread of suggestively associated loci, indicate that genetic influence is of polygenic nature. Nevertheless, persistence to MTX monotherapy was lower in patients with a greater genetic disposition, per the PRS, towards RA.
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