| 31. |
- Kettunen, Petronella
(författare)
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Neuromodulation within a spinal locomotor network : role of metabotropic glutamate receptor subtypes
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The metabotropic glutamate receptors, mGluRs, are G-protein coupled receptors. They consist of eight cloned subtypes, which are divided into three groups depending on the amino acid sequence similarity, pharmacology and their signal pathways. In the lamprey spinal cord, group I mGluRs are located postsynaptically, while group II and III are presynaptic and depress synaptic transmission. The goal of this thesis has been to elucidate the mechanisms by which the two subtypes of group I mGluRs, i.e. mGluR1 and mGluR5, modulate the firing properties of single neurons, the synaptic interactions and the overall activity of the spinal locomotor network in the lamprey. mGluR1 activation by endogenously released glutamate increases the frequency of the locomotor rhythm induced by NMDA in the isolated lamprey spinal cord preparation. This increase in the frequency is the result of a number of cellular and molecular mechanisms that have been studied in detail. Firstly, mGIuR1 potentiates the NMDA-induced current and modulates NMDAinduced TTX-resistant membrane potential oscillations known to occur during locomotion. Mathematical simulations of the interaction between mGluR1 and NMDA receptors reproduce the modulation of the NMDA-induced oscillations and the increase in the locomotor frequency. Secondly, mGluR1 activation depolarizes the membrane potential of neurons and consequently induces repetitive firing. These effects are due to an inhibition of a leak current responsible for setting the resting membrane potential. Interestingly, mGluR1 activates different signaling pathways to modulate NMDA current and leak conductance. Both effects require activation of Gproteins. The mGluR1-mediated inhibition of leak current requires PLC activation and release of Ca2+ from internal stores, as well as tyrosine kinase activation. The potentiation of NMDA current is not, however, dependent on an increase in intracellular Ca2+ or on tyrosine kinases. Thirdly, activation of mGluR1 receptors gives rise to a synthesis and release of endocannabinoids from postsynaptic neurons. The released endocannabinoids act as retrograde messengers which bind to presynaptic receptors and reduce glycinergic synaptic transmission. The reduced inhibitory transmission will result in an increase in the locomotor frequency. Hence, mGluR1 activation triggers the release of endocannabinoids which thus contribute to the mGlur1 mediated modulation of the locomotor network operation. Finally, endogenous activation of mGluR5 during locomotion decreases the burst frequency and produces long-lasting oscillations of the intracellular Ca2+ concentration. These oscillations are mediated through PLC and Ca2+ release from internal stores. Furthermore, they are also dependent on Ca2+ influx through L-type Ca2+ channels but do not involve PKC activation. Thus, mGluR5 seems to modulate the locomotor frequency via mechanisms involving oscillations of intracellular Ca 2+ concentration. In conclusion, the two group I mGluRs subtypes, mGluR1 and mGluR5, use separate signaling pathways and mediate opposite effects on locomotor activity. While the modulatory effects of mGluR5 seems to involve Ca2+ oscillations, those of rnGluR1 depend on different cellular and synaptic mechanisms which act in a synergistic manner to regulate the locomotor frequency.
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| 32. |
- Kim, Min, et al.
(författare)
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Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort
- 2019
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Ingår i: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 15:6, s. 817-827
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers.METHODS: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis.RESULTS: Eight metabolites were associated with amyloid β and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory.DISCUSSION: PFAMs have been found increased and associated with amyloid β burden in CSF and clinical measures.
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| 33. |
- Landgren, Sara, 1980, et al.
(författare)
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A novel ARC gene polymorphism is associated with reduced risk of Alzheimer's disease
- 2012
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Ingår i: Journal of Neural Transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 119:7, s. 833-842
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid beta (A beta) peptides in plaques in the brain. Recent studies have shown the links between AD and the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein), involved in synaptic plasticity and memory consolidation. For example, AD mouse models show a decreased expression of Arc mRNA in the brain. In additional, acute A beta application to brain slices leads to a widespread ARC protein diffusion, unlike the normal defined localization to synapses. In this study, we investigated genetic variation in human ARC and the risk of developing AD. To this end, we genotyped 713 subjects diagnosed with AD and 841 controls without dementia. ARC was sequenced in a group of healthy individuals, and seven previously known SNPs and three novel SNPs were identified. Two of the newly found SNPs were intronic and one, +2852(G/A), was located in the 3'UTR. Three tag SNPs were selected, including the novel SNP +2852(G/A), to relate to risk of AD, Mini Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau181 (P-tau(181)) and A beta(1-42). The AA genotype of the newly found 3'-UTR SNP +2852(A/G), was associated with a decreased risk of AD (p (c) = 0.005; OR = 0.74; 95 % CI: 0.61-0.89). No associations of single SNPs or haplotypes with MMSE score or CSF biomarkers were found. Here we report a novel ARC SNP associated with a reduced risk of developing AD. To our knowledge, this is the first study associating a gene variant of ARC with any disease. The location of the SNP within the 3'UTR indicates that dendritic targeting of ARC mRNA could be involved in the molecular mechanisms underlying this protective function. However, further investigation of the importance of this SNP for ARC function, ARC processing and the pathology of AD is needed.
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| 34. |
- Landin, Jenny, et al.
(författare)
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Oxytocin Receptors Regulate Social Preference in Zebrafish.
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- With a strong tendency to socialise, the zebrafish is a useful model to study social behaviour, with implications for better treatments of social impairments, for instance in autism spectrum disorders. Although oxytocin is crucial for social behaviour in mammals, the importance of the fish orthologue - isotocin or zebrafish oxytocin (zOT) - for social behaviour in zebrafish is unclear. The aims of this study were firstly, to elucidate the receptor specificity of zOT and the related vasotocin or zebrafish vasopressin (zVP; the orthologue of mammalian vasopressin) and the nonpeptidergic oxytocin receptor antagonist L-368,899, and secondly to investigate if L-368,899 inhibits social preference in zebrafish. The potencies of ligands were evaluated for zOT/zVP family receptors in HEK293 cells. Adult and larval zebrafish were treated with L-368,899 or vehicle and subsequently assessed for social behaviour and anxiety (adults only). The antagonist L-368,899 specifically inhibited the two zOT receptors, but not the two zVP-1 receptors. The antagonist decreased social preference in adult and larval zebrafish. It did not affect anxiety in adults. These results indicate that endogenous zOT, and possibly zVP, is involved in social behaviour in zebrafish via either or both of the two zOT receptors, and show promise for future explorations of the anatomy and evolution of networks underlying social behaviour.
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| 35. |
- Larsson, Susanna, et al.
(författare)
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Orthotopic Transplantation of Human Paediatric High-Grade Glioma in Zebrafish Larvae
- 2022
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Ingår i: Brain Sciences. - : MDPI AG. - 2076-3425. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Brain tumours are the most common cause of death among children with solid tumours, and high-grade gliomas (HGG) are among the most devastating forms with very poor outcomes. In the search for more effective treatments for paediatric HGG, there is a need for better experimental models. To date, there are no xenograft zebrafish models developed for human paediatric HGG; existing models rely on adult cells. The use of paediatric models is of great importance since it is well known that the genetic and epigenetic mechanisms behind adult and paediatric disease differ greatly. In this study, we present a clinically relevant in vivo model based on paediatric primary glioma stem cell (GSC) cultures, which after orthotopic injection into the zebrafish larvae, can be monitored using confocal imaging over time. We show that cells invade the brain tissue and can be followed up to 8 days post-injection while they establish in the fore/mid brain. This model offers an in vivo system where tumour invasion can be monitored and drug treatments quickly be evaluated. The possibility to monitor patient-specific cells has the potential to contribute to a better understanding of cellular behaviour and personalised treatments in the future.
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| 36. |
- Melin, Jeanette, et al.
(författare)
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Entropy-based explanations of serial position and learning effects in ordinal responses to word list tests
- 2023
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Ingår i: Acta IMEKO. - 2221-870X. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Measuring a person’s cognitive abilities, such as memory and learning, is central in many medical conditions to reliably diagnose, treat and monitor disease progression. Common tests typically include tasks of recalling sequences of blocks, digits or words. Recalling a word list is affected by so-called serial position effects (SPE), meaning that words at the beginning or end of the list are more likely to be recalled. In our earlier work, as part of including ordinal and nominal properties in metrology, compensation for ordinality in the raw test scores has been performed with psychometric Rasch measurement theory. Thereafter, SPE have been successfully explained with construct specification equations (CSE) dominated by information theoretical entropy as candidate reference measurement procedures. Here, we present how previous German results for explaining memory difficulty in the immediate recalling (IR, trial 1) task of the Rey’s Auditory Verbal Learning Test (RAVLT) can be replicated with a Swedish cohort (the Gothenburg Mild Cognitive Impairment study, n = 251). This CSE replicability for RAVLT demonstrates comparability across the two cohorts in a kind of inter-laboratory study. Moreover, RAVLT includes repeated trials and learning through practice is expected. How memory task difficulty changes over the eight trials in RAVLT is studied: SPE are not so prominent for the delayed recalling sequences and there is an overall reduction in the task difficulty CSE intercept with trial number, interpreted as an effect of learning. To conclude, the methodology and evidence provided here can be clinically used not only to measure a person’s memory ability but also his or her learning ability, as well as understanding the relationship between learning ability and other cognitive domains.
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| 37. |
- Minta, Karolina, et al.
(författare)
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Brevican and Neurocan Peptides as Potential Cerebrospinal Fluid Biomarkers for Differentiation Between Vascular Dementia and Alzheimer's Disease
- 2021
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Ingår i: Journal of Alzheimer's disease : JAD. - 1387-2877 .- 1875-8908. ; 79:2, s. 729-741
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Brevican and neurocan are central nervous system-specific extracellular matrix proteoglycans. They are degraded by extracellular enzymes, such as metalloproteinases. However, their degradation profile is largely unexplored in cerebrospinal fluid (CSF).OBJECTIVE: The study aim was to quantify proteolytic peptides derived from brevican and neurocan in human CSF of patients with Alzheimer's disease (AD) and vascular dementia (VaD) compared with controls.METHODS: The first cohort consisted of 75 individuals including 25 patients with AD, 7 with mild cognitive impairment (MCI) diagnosed with AD upon follow-up, 10 patients with VaD or MCI diagnosed with VaD upon follow-up, and 33 healthy controls and cognitively stable MCI patients. In the second cohort, 31 individuals were included (5 AD patients, 14 VaD patients and 12 healthy controls). Twenty proteolytic peptides derived from brevican (n = 9) and neurocan (n = 11) were quantified using high-resolution parallel reaction monitoring mass spectrometry.RESULTS: In the first cohort, the majority of CSF concentrations of brevican and neurocan peptides were significantly decreased inVaDas compared withADpatients (AUC = 0.83.0.93, p≤0.05) and as compared with the control group (AUC = 0.79.0.87, p ≤ 0.05). In the second cohort, CSF concentrations of two brevican peptides (B87, B156) were significantly decreased in VaD compared with AD (AUC = 0.86.0.91, p ≤ 0.05) and to controls (AUC = 0.80.0.82, p ≤ 0.05), while other brevican and neurocan peptides showed a clear trend to be decreased in VaD compared with AD (AUC = 0.64.80, p > 0.05). No peptides differed between AD and controls.CONCLUSION: Brevican and neurocan peptides are potential diagnostic biomarkers for VaD, with ability to separate VaD from AD.
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| 38. |
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| 39. |
- Radomska, Katarzyna J., et al.
(författare)
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Characterization and Expression of the Zebrafish qki Paralogs
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Quaking (QKI) is an RNA-binding protein involved in post-transcriptional mRNA processing. This gene is found to be associated with several human neurological disorders. Early expression of QKI proteins in the developing mouse neuroepithelium, together with neural tube defects in Qk mouse mutants, suggest the functional requirement of Qk for the establishment of the nervous system. As a knockout of Qk is embryonic lethal in mice, other model systems like the zebrafish could serve as a tool to study the developmental functions of qki. In the present study we sought to characterize the evolutionary relationship and spatiotemporal expression of qkia, qki2, and qkib; zebrafish homologs of human QKI. We found that qkia is an ancestral paralog of the single tetrapod Qk gene that was likely lost during the fin-to-limb transition. Conversely, qkib and qki2 are orthologs, emerging at the root of the vertebrate and teleost lineage, respectively. Both qki2 and qkib, but not qkia, were expressed in the progenitor domains of the central nervous system, similar to expression of the single gene in mice. Despite having partially overlapping expression domains, each gene has a unique expression pattern, suggesting that these genes have undergone subfunctionalization following duplication. Therefore, we suggest the zebrafish could be used to study the separate functions of qki genes during embryonic development.
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| 40. |
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