| 1. |
- Abrahamsson, Therése, 1976, et al.
(författare)
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AMPA silencing is a prerequisite for developmental long-term potentiation in the hippocampal CA1 region.
- 2008
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Ingår i: Journal of neurophysiology. - : American Physiological Society. - 0022-3077 .- 1522-1598.
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Tidskriftsartikel (refereegranskat)abstract
- AMPA unsilencing is an often proposed expression mechanism both for developmental LTP, involved in circuitry refinement during brain development, and for mature LTP, involved in learning and memory. In the hippocampal CA3-CA1 connection naïve (non-stimulated) synapses are AMPA-signaling, and AMPA-silent synapses are created from naïve AMPA-signaling (AMPA-labile) synapses by test pulse synaptic activation (AMPA silencing). To investigate to what extent LTP at different developmental stages are explained by AMPA unsilencing, the amount of LTP obtained at these different developmental stages was related to the amount of AMPA silencing that preceded the induction of LTP. When examined in the second postnatal week Hebbian induction was found to produce no more stable potentiation than that causing a return to the naïve synaptic strength existing prior to the AMPA silencing. Moreover, in the absence of a preceding AMPA silencing Hebbian induction produced no stable potentiation above the naïve synaptic strength. Thus, this early, or developmental, LTP is nothing more than an unsilencing (de-depression), and stabilization, of the AMPA signaling that was lost by the prior AMPA silencing. This de-depression and stabilization of AMPA signaling was mimicked by the presence of the PKA-activator forskolin. As the relative degree of AMPA silencing decreased with development, LTP manifested itself more and more as a "genuine" potentiation (as opposed to a de-depression) not explained by unsilencing and stabilization of AMPA-labile synapses. This "genuine", or mature, LTP rose from close to nothing of total LTP prior to P13, to about 70 % of total LTP at P16, and to about 90 % of total LTP at P30. Developmental LTP, by stabilization of AMPA labile synapses, thus seems adapted to select synaptic connections to the growing synaptic network. Mature LTP, by instead strengthening existing stable connections between cells, may then create functionally tightly connected cell assemblies within this network.
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| 2. |
- Abrahamsson, Therése, 1976, et al.
(författare)
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Reversible synaptic depression in developing rat CA3-CA1 synapses explained by a novel cycle of AMPA silencing-unsilencing
- 2007
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Ingår i: JOURNAL OF NEUROPHYSIOLOGY. - : American Physiological Society. - 0022-3077 .- 1522-1598. ; 98:5, s. 2604-2611
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Tidskriftsartikel (refereegranskat)abstract
- In the developing hippocampus, experiments using whole cell recordings have shown that a small number of synaptic activations can convert many glutamate synapses to AMPA silent synapses. This depression of AMPA signaling is induced by low-frequency (0.05–0.2 Hz) activation, does not require N-methyl-d-aspartate or metabotropic glutamate receptor activation for its induction, and does not readily reverse after stimulus interruption. Here we show, using field recordings and perforated patch-clamp recordings of transmission in developing CA3–CA1 synapses, that this synaptic depression also can be observed under more noninvasive recording conditions. Moreover, under these conditions, the synaptic depression spontaneously recovers within 20 min by the absence of synaptic activation alone, with a time constant of ∼7 min as determined by field excitatory postsynaptic potential recordings. Thus as for the expression of long-term potentiation (LTP), recovery from this depression is susceptible to whole cell dialysis (“wash-out”). In contrast to LTP-induced unsilencing, the AMPA signaling after stimulus interruption was again labile, resumed stimulation resulted in renewed depression. The present study has thus identified a novel cycle for AMPA signaling in which the nascent glutamate synapse cycles between an AMPA silent state, induced by a small number of synaptic activations, and a labile AMPA signaling, induced by prolonged inactivity.
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| 3. |
- Abrahamsson, Therése, 1976, et al.
(författare)
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Synaptic fatigue at the naive perforant path-dentate granule cell synapse in the rat.
- 2005
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Ingår i: The Journal of physiology. - : Wiley. - 0022-3751. ; 569:Pt 3, s. 737-50
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Tidskriftsartikel (refereegranskat)abstract
- Synaptic activation at low frequency is often used to probe synaptic function and synaptic plasticity, but little is known about how such low-frequency activation itself affects synaptic transmission. In the present study, we have examined how the perforant path-dentate granule cell (PP-GC) synapse adapts to low-frequency activation from a previously non-activated (naive) state. Stimulation at 0.2 Hz in acute slices from developing rats (7-12 days old) caused a gradual depression of the AMPA EPSC (at -80 mV) to about half within 50 stimuli. This synaptic fatigue was unaffected by the NMDA and metabotropic glutamate (mGlu) receptor antagonists d-AP5 and LY-341495. A smaller component of this synaptic fatigue was readily reversible when switching to very low-frequency stimulation (0.033-0.017 Hz) and is attributed to a reversible decrease in release probability, which is probably due to depletion of readily releasable vesicles. Thus, it was expressed to the same extent by AMPA and NMDA EPSCs, and was associated with a decrease in quantal content (measured as 1/CV(2)) with no change in the paired-pulse ratio. The larger component of the synaptic fatigue was not readily reversible, was selective for AMPA EPSCs and was associated with a decrease in 1/CV(2), thus probably representing silencing of AMPA signalling in a subset of synapses. In adult rats (> 30 days old), the AMPA silencing had disappeared while the low-frequency depression remained unaltered. The present study has thus identified two forms of synaptic plasticity that contribute to fatigue of synaptic transmission at low frequencies at the developing PP-GC synapse; AMPA silencing and a low-frequency depression of release probability.
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| 4. |
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| 5. |
- Andersson, My, 1980, et al.
(författare)
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Astrocyte-mediated short-term synaptic depression in the rat hippocampal CA1 area: two modes of decreasing release probability.
- 2011
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Ingår i: BMC neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Synaptic burst activation feeds back as a short-term depression of release probability at hippocampal CA3-CA1 synapses. This short-term synaptic plasticity requires functional astrocytes and it affects both the recently active (< 1 s) synapses (post-burst depression) as well as inactive neighboring synapses (transient heterosynaptic depression). The aim of this study was to investigate and compare the components contributing to the depression of release probability in these two different scenarios. RESULTS: When tested using paired-pulses, following a period of inactivity, the transient heterosynaptic depression was expressed as a reduction in the response to only the first pulse, whereas the response to the second pulse was unaffected. This selective depression of only the first response in a high-frequency burst was shared by the homosynaptic post-burst depression, but it was partially counteracted by augmentation at these recently active synapses. In addition, the expression of the homosynaptic post-burst depression included an astrocyte-mediated reduction of the pool of release-ready primed vesicles. CONCLUSIONS: Our results suggest that activated astrocytes depress the release probability via two different mechanisms; by depression of vesicular release probability only at inactive synapses and by imposing a delay in the recovery of the primed pool of vesicles following depletion. These mechanisms restrict the expression of the astrocyte-mediated depression to temporal windows that are typical for synaptic burst activity.
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| 6. |
- Andersson, My, 1980, et al.
(författare)
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Astrocytes impose postburst depression of release probability at hippocampal glutamate synapses.
- 2010
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 30:16, s. 5776-80
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Tidskriftsartikel (refereegranskat)abstract
- Many neurons typically fire action potentials in brief, high-frequency bursts with specific consequences for their synaptic output. Here we have examined short-term plasticity engaged during burst activation using electrophysiological recordings in acute rat hippocampal slices. We show that CA3-CA1 glutamate synapses exhibit a prominent depression of presynaptic release probability for approximately 1 s after such a burst. This postburst depression exhibits a distinct cooperativity threshold, is abolished by inhibiting astrocyte metabolism and astrocyte calcium signaling, and is not operational in the developing hippocampus. Our results suggest that astrocytes are actively involved in short-term synaptic depression, shaping synaptic activity during behaviorally relevant neural activity.
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| 7. |
- Andersson, My, 1980, et al.
(författare)
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Astrocytes play a critical role in transient heterosynaptic depression in the rat hippocampal CA1 region.
- 2007
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Ingår i: The Journal of physiology. - : Wiley. - 0022-3751. ; 585:Pt 3, s. 843-52
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Tidskriftsartikel (refereegranskat)abstract
- Active synapses can reduce the probability of transmitter release at neighbouring synapses. Depending on whether such heterosynaptic depression is mediated by intersynaptic diffusion of transmitter or by release of gliotransmitters, astrocytes should either hinder or promote the heterosynaptic depression. In the present study we have examined the developmental profile and astrocytic involvement in a transient heterosynaptic depression (tHeSD) in the CA1 region of the rat hippocampal slice preparation. A short stimulus burst (3 impulses at 50 Hz) to one group of synapses elicited a depression of the field EPSP evoked in another group of synapses that amounted to about 25% 0.5 s after the conditioning burst. This tHeSD was associated with an increase in the paired-pulse ratio of about 30%. The tHeSD was not present in slices from rats younger than 10 postnatal days and developed towards the adult magnitude between postnatal days 10 and 20. The tHeSD was totally prevented by the glia-specific toxin fluoroacetate (FAC), by carbenoxolone, a general blocker of connexin-based channels, and by endothelin, an endogenous peptide that has been shown to block astrocytic connexin-based channels. Antagonists to GABA(B) receptors and group II/III metabotropic glutamate receptors (mGluRs) abolished the tHeSD whereas antagonists to NMDA- and adenosine A1 receptors, and to group I mGluRs, did not affect the tHeSD. These results suggest that the tHeSD relies on GABA(B) receptors, group II/III mGluRs and on gliotransmitter release from functionally mature astrocytes.
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| 8. |
- Bergström, Petra, et al.
(författare)
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Amyloid precursor protein expression and processing are differentially regulated during cortical neuron differentiation
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid precursor protein (APP) and its cleavage product amyloid beta (A beta) have been thoroughly studied in Alzheimer's disease. However, APP also appears to be important for neuronal development. Differentiation of induced pluripotent stem cells (iPSCs) towards cortical neurons enables in vitro mechanistic studies on human neuronal development. Here, we investigated expression and proteolytic processing of APP during differentiation of human iPSCs towards cortical neurons over a 100-day period. APP expression remained stable during neuronal differentiation, whereas APP processing changed. alpha-Cleaved soluble APP (sAPP alpha) was secreted early during differentiation, from neuronal progenitors, while beta-cleaved soluble APP (sAPP beta) was first secreted after deep-layer neurons had formed. Short A beta peptides, including A beta 1-15/16, peaked during the progenitor stage, while processing shifted towards longer peptides, such as A beta 1-40/42, when post-mitotic neurons appeared. This indicates that APP processing is regulated throughout differentiation of cortical neurons and that amyloidogenic APP processing, as reflected by A beta 1-40/42, is associated with mature neuronal phenotypes.
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| 9. |
- Björefeldt, Andreas, 1982, et al.
(författare)
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Human cerebrospinal fluid increases the excitability of pyramidal neurons in the in vitro brain slice.
- 2015
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Ingår i: The Journal of physiology. - : Wiley. - 1469-7793 .- 0022-3751. ; 593:1, s. 231-43
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Tidskriftsartikel (refereegranskat)abstract
- The cerebrospinal fluid contains numerous neuromodulators at ambient levels but whether, and how, they affect the activity of central neurons is unknown. This study provides experimental evidence that human cerebrospinal fluid (hCSF) increases the excitability of hippocampal and neocortical pyramidal neurons. Hippocampal CA1 pyramidal neurons in hCSF displayed lowered firing thresholds, depolarized resting membrane potentials and reduced input resistance, mimicking properties of pyramidal neurons recorded in vivo. The excitability-increasing effect of hCSF on CA1 pyramidal neurons was entirely occluded by intracellular application of GTPγS, suggesting that neuromodulatory effects were mediated by G-protein coupled receptors. These results indicate that the CSF promotes spontaneous excitatory neuronal activity, and may help to explain observed differences in the activity of pyramidal neurons recorded in vivo and in vitro.
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| 10. |
- Björefeldt, Andreas, 1982, et al.
(författare)
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Human cerebrospinal fluid promotes spontaneous gamma oscillations in the hippocampus in vitro
- 2020
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Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 30:2, s. 101-113
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Tidskriftsartikel (refereegranskat)abstract
- Gamma oscillations (30-80 Hz) are fast network activity patterns frequently linked to cognition. They are commonly studied in hippocampal brain slices in vitro, where they can be evoked via pharmacological activation of various receptor families. One limitation of this approach is that neuronal activity is studied in a highly artificial extracellular fluid environment, as provided by artificial cerebrospinal fluid (aCSF). Here, we examine the influence of human cerebrospinal fluid (hCSF) on kainate-evoked and spontaneous gamma oscillations in mouse hippocampus. We show that hCSF, as compared to aCSF of matched electrolyte and glucose composition, increases the power of kainate-evoked gamma oscillations and induces spontaneous gamma activity in areas CA3 and CA1 that is reversed by washout. Bath application of atropine entirely abolished hCSF-induced gamma oscillations, indicating critical contribution from muscarinic acetylcholine receptor-mediated signaling. In separate whole-cell patch clamp recordings from rat hippocampus, hCSF increased theta resonance frequency and strength in pyramidal cells along with enhancement of h-current (I-h) amplitude. We found no evidence of intrinsic gamma frequency resonance at baseline (aCSF) among fast-spiking interneurons, and this was not altered by hCSF. However, hCSF increased the excitability of fast-spiking interneurons, which likely contributed to gamma rhythmogenesis. Our findings show that hCSF promotes network gamma oscillations in the hippocampus in vitro and suggest that neuromodulators distributed in CSF could have significant influence on neuronal network activity in vivo.
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| 11. |
- Björefeldt, Andreas, 1982, et al.
(författare)
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Neuromodulation of fast-spiking and non-fast-spiking hippocampal CA1 interneurons by human cerebrospinal fluid.
- 2016
-
Ingår i: The Journal of physiology. - 1469-7793. ; 594:4, s. 937-52
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Tidskriftsartikel (refereegranskat)abstract
- GABAergic interneurons intricately regulate the activity of hippocampal and neocortical networks. Their function in vivo is likely to be tuned by neuromodulatory substances in brain extracellular fluid. However, in vitro investigations of GABAergic interneuron function do not account for such effects, as neurons are kept in artificial extracellular fluid. To examine the neuromodulatory influence of brain extracellular fluid on GABAergic activity, we recorded from fast-spiking and non-fast-spiking CA1 interneurons, as well as from pyramidal cells, in the presence of human cerebrospinal fluid (hCSF), using a matched artificial cerebrospinal (aCSF) fluid as control. We found that hCSF increased the frequency of spontaneous firing more than twofold in the two groups of interneurons, and more than fourfold in CA1 pyramidal cells. hCSF did not affect the resting membrane potential of CA1 interneurons but caused depolarization in pyramidal cells. The increased excitability of interneurons and pyramidal cells was accompanied by reductions in afterhyperpolarization amplitudes and a left-shift in the frequency-current relationships. Our results suggest that ambient concentrations of neuromodulators in the brain extracellular fluid powerfully influence the excitability of neuronal networks. This article is protected by copyright. All rights reserved.
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| 12. |
- Björefeldt, Andreas, 1982, et al.
(författare)
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Neuromodulation via the Cerebrospinal Fluid: Insights from Recent in Vitro Studies.
- 2018
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Ingår i: Frontiers in neural circuits. - : Frontiers Media SA. - 1662-5110. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- The cerebrospinal fluid (CSF) occupies the brain's ventricles and subarachnoid space and, together with the interstitial fluid (ISF), forms a continuous fluidic network that bathes all cells of the central nervous system (CNS). As such, the CSF is well positioned to actively distribute neuromodulators to neural circuitsin vivovia volume transmission. Recentin vitroexperimental work in brain slices and neuronal cultures has shown that human CSF indeed contains neuromodulators that strongly influence neuronal activity. Here we briefly summarize these new findings and discuss their potential relevance to neural circuits in health and disease.
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| 13. |
- Blomstrand, Fredrik, 1969, et al.
(författare)
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Endothelins regulate astrocyte gap junctions in rat hippocampal slices.
- 2004
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Ingår i: The European journal of neuroscience. - 0953-816X. ; 19:4, s. 1005-15
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Tidskriftsartikel (refereegranskat)abstract
- Gap junctional communication (GJC) is a typical feature of astrocytes proposed to contribute to the role played by these glial cells in brain physiology and pathology. In acutely isolated hippocampal slices from rat (P11-P19), intercellular diffusion of biocytin through gap junction channels was shown to occur between hundreds of cells immuno-positive for astrocytic markers studied in the CA1/CA2 region. Single-cell RT-PCR demonstrated astrocytic mRNA expression of several connexin (Cx) subtypes, the molecular constituent of gap junction channels, whereas immunoblotting confirmed that Cx43 and Cx30 are the main gap junction proteins in hippocampal astrocytes. In the brain, astrocytes represent a major target for endothelins (Ets), a vasoactive family of peptides. Our results demonstrate that Ets decrease the expression of phosphorylated Cx43 forms and are potent inhibitors of GJC. The Et-induced effects were investigated using specific Et receptor agonists and antagonists, including Bosentan (Tracleer trade mark ), an EtA/B receptor antagonist, and using hippocampal slices and cultures from EtB-receptor-deficient rats. Interestingly, the pharmacological profile of Ets effects did not follow the classical profile established in cardiovascular systems. The present study therefore identifies Ets as potent endogenous inhibitory regulators of astrocyte networks. As such, the action of these peptides on astrocyte GJC might be involved in the contribution of astrocytes to neuroprotective processes and have a therapeutic potential in neuropathological situations.
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| 14. |
- Brederlau, Anke, 1968, et al.
(författare)
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Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson's disease: effect of in vitro differentiation on graft survival and teratoma formation.
- 2006
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Ingår i: Stem cells (Dayton, Ohio). - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 24:6, s. 1433-40
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Tidskriftsartikel (refereegranskat)abstract
- Human embryonic stem cells (hESCs) have been proposed as a source of dopamine (DA) neurons for transplantation in Parkinson's disease (PD). We have investigated the effect of in vitro predifferentiation on in vivo survival and differentiation of hESCs implanted into the 6-OHDA (6-hydroxydopamine)-lesion rat model of PD. The hESCs were cocultured with PA6 cells for 16, 20, or 23 days, leading to the in vitro differentiation into DA neurons. Grafted hESC-derived cells survived well and expressed neuronal markers. However, very few exhibited a DA neuron phenotype. Reversal of lesion-induced motor deficits was not observed. Rats grafted with hESCs predifferentiated in vitro for 16 days developed severe teratomas, whereas most rats grafted with hESCs predifferentiated for 20 and 23 days remained healthy until the end of the experiment. This indicates that prolonged in vitro differentiation of hESCs is essential for preventing formation of teratomas.
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| 15. |
- Daborg, Jonny, et al.
(författare)
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Cerebrospinal fluid levels of complement proteins C3, C4 and CR1 in Alzheimer's disease.
- 2012
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Ingår i: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 1435-1463 .- 0300-9564. ; 119:7, s. 789-97
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is strongly associated with loss of synapses. The complement system has been shown to be involved in synaptic elimination. Several studies point to an association between AD and the complement system. The purpose of this study was to examine the association of cerebrospinal fluid (CSF) levels of complement components 3 and 4 (C3 and C4, respectively), and complement receptor 1 (CR1) with AD in 43 patients with AD plus dementia, 42 patients with mild cognitive impairment (MCI) who progressed to AD during follow-up (MCI-AD), 42 patients with stable MCI and 44 controls. Complement levels were also applied in a multivariate model to determine if they provided any added value to the core AD biomarkers Aβ42, T-tau and P-tau. We found elevated CSF levels of C3 and C4 in AD compared with MCI without progression to AD, and elevated CSF levels of CR1 in MCI-AD and AD when these groups were merged. These results provide support for aberrant complement regulation as a part in the AD process, but the changes are not diagnostically useful.
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| 16. |
- Daborg, Jonny, et al.
(författare)
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Complement Gene Single Nucleotide Polymorphisms and Biomarker Endophenotypes of Alzheimer's Disease
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877. ; 35:1, s. 51-57
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Tidskriftsartikel (refereegranskat)abstract
- The complement system has been implicated in both physiological synapse elimination and Alzheimer's disease (AD). Here, we investigated associations between four single nucleotide polymorphisms (SNPs) in complement genes and cerebrospinal fluid (CSF) biomarkers for AD in 452 neurochemically or neuropathologically verified AD cases and 678 cognitively normal controls. None of the SNPs associated with risk of AD but there were potential associations of rs9332739 in the C2 gene and rs4151667 in the complement factor B gene with CSF tau levels (p = 0.023) and Mini-Mental State Examination scores (p = 0.012), both of which may be considered markers of disease intensity/severity.
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| 17. |
- Dahlin, Emelie, et al.
(författare)
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Effects of physical exercise and stress on hippocampal CA1 and dentate gyrus synaptic transmission and long-term potentiation in adolescent and adult Wistar rats
- 2019
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Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522. ; 408, s. 22-30
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Tidskriftsartikel (refereegranskat)abstract
- It is commonly recognized that physical exercise positively affects several CNS regions and improves cognitive abilities. For example, exercise is associated with an increase in neurogenesis and facilitation of long-term potentiation in the hippocampus. Conversely, animal models for depression are associated with a decrease in neurogenesis and a reduction of long-term potentiation in the hippocampus. Although exercise could be a viable option in the treatment of some forms of depression, the mechanisms responsible for such improvements have not been elucidated. In this study, we examine hippocampal function using electrophysiological field recordings in CA1 and dentate gyrus to study baseline synaptic transmission and long-term potentiation in adolescent and adult rats prenatally exposed to the glucocorticoid dexamethasone. One group of animals was allowed to run voluntarily for 10 or 21 days using an exercise wheel before the experiments, and the control group was prevented from running (i.e. the exercise wheel was locked). In adult saline-exposed animals, exercise was associated with increased long-term potentiation in the dentate gyrus. Unexpectedly, in dexamethasone-exposed animals, dentate gyrus long-term potentiation was facilitated, whereas long-term potentiation in CA1 was unaffected by prenatal dexamethasone or by 10 or 21 days of voluntary running. Irrespective of age, prenatal dexamethasone and running had limited effects on synaptic transmission and presynaptic release in CA1 and dentate gyrus. In summary, running facilitates dentate gyrus long-term potentiation in adult animals that resembles the effects of prenatal dexamethasone. © 2019 Elsevier Ltd
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| 18. |
- Dupuis, Julien P, et al.
(författare)
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Surface dynamics of GluN2B-NMDA receptors controls plasticity of maturing glutamate synapses.
- 2014
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Ingår i: The EMBO journal. - : Wiley. - 1460-2075 .- 0261-4189. ; 33:8, s. 842-861
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Tidskriftsartikel (refereegranskat)abstract
- NMDA-type glutamate receptors (NMDAR) are central actors in the plasticity of excitatory synapses. During adaptive processes, the number and composition of synaptic NMDAR can be rapidly modified, as in neonatal hippocampal synapses where a switch from predominant GluN2B- to GluN2A-containing receptors is observed after the induction of long-term potentiation (LTP). However, the cellular pathways by which surface NMDAR subtypes are dynamically regulated during activity-dependent synaptic adaptations remain poorly understood. Using a combination of high-resolution single nanoparticle imaging and electrophysiology, we show here that GluN2B-NMDAR are dynamically redistributed away from glutamate synapses through increased lateral diffusion during LTP in immature neurons. Strikingly, preventing this activity-dependent GluN2B-NMDAR surface redistribution through cross-linking, either with commercial or with autoimmune anti-NMDA antibodies from patient with neuropsychiatric symptoms, affects the dynamics and spine accumulation of CaMKII and impairs LTP. Interestingly, the same impairments are observed when expressing a mutant of GluN2B-NMDAR unable to bind CaMKII. We thus uncover a non-canonical mechanism by which GluN2B-NMDAR surface dynamics plays a critical role in the plasticity of maturing synapses through a direct interplay with CaMKII.
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| 19. |
- Espana, A., et al.
(författare)
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Alteration of NMDA receptor trafficking as a cellular hallmark of psychosis
- 2021
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- A dysfunction of the glutamatergic transmission, especially of the NMDA receptor (NMDAR), constitutes one of the main biological substrate of psychotic disorders, such as schizophrenia. The NMDAR signaling hypofunction, through genetic and/or environmental insults, would cause a neurodevelopmental myriad of molecular, cellular, and network alterations that persist throughout life. Yet, the mechanisms underpinning NMDAR dysfunctions remain elusive. Here, we compared the membrane trafficking of NMDAR in three gold-standard models of schizophrenia, i.e., patient's cerebrospinal fluids, genetic manipulations of susceptibility genes, and prenatal developmental alterations. Using a combination of single nanoparticle tracking, electrophysiological, biochemical, and behavioral approaches in rodents, we identified that the NMDAR trafficking in hippocampal neurons was consistently altered in all these different models. Artificial manipulations of the NMDAR surface dynamics with competing ligands or antibody-induced receptor cross-link in the developing rat brain were sufficient to regulate the adult acoustic startle reflex and compensate for an early pathological challenge. Collectively, we show that the NMDAR trafficking is markedly altered in all clinically relevant models of psychosis, opening new avenues of therapeutical strategies.
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| 20. |
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| 21. |
- Faijerson, Jonas, 1977, et al.
(författare)
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Adult neural stem/progenitor cells reduce NMDA-induced excitotoxicity via the novel neuroprotective peptide pentinin.
- 2009
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Ingår i: Journal of neurochemistry. - 1471-4159. ; 109:3, s. 858-66
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Tidskriftsartikel (refereegranskat)abstract
- Although the potential of adult neural stem cells to repair damage via cell replacement has been widely reported, the ability of endogenous stem cells to positively modulate damage is less well studied. We investigated whether medium conditioned by adult hippocampal stem/progenitor cells altered the extent of excitotoxic cell death in hippocampal slice cultures. Conditioned medium significantly reduced cell death following 24 h of exposure to 10 microM NMDA. Neuroprotection was greater in the dentate gyrus, a region neighboring the subgranular zone where stem/progenitor cells reside compared with pyramidal cells of the cornis ammonis. Using mass spectrometric analysis of the conditioned medium, we identified a pentameric peptide fragment that corresponded to residues 26-30 of the insulin B chain which we termed 'pentinin'. The peptide is a putative breakdown product of insulin, a constituent of the culture medium, and may be produced by insulin-degrading enzyme, an enzyme expressed by the stem/progenitor cells. In the presence of 100 pM of synthetic pentinin, the number of mature and immature neurons killed by NMDA-induced toxicity was significantly reduced in the dentate gyrus. These data suggest that progenitors in the subgranular zone may convert exogenous insulin into a peptide capable of protecting neighboring neurons from excitotoxic injury.
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| 22. |
- Forsberg, My, et al.
(författare)
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Ionized calcium in human cerebrospinal fluid and its influence on intrinsic and synaptic excitability of hippocampal pyramidal neurons in the rat.
- 2019
-
Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 149:4, s. 452-470
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Tidskriftsartikel (refereegranskat)abstract
- It is well-known that the extracellular concentration of calcium affects neuronal excitability and synaptic transmission. Less is known about the physiological concentration of extracellular calcium in the brain. In electrophysiological brain slice experiments, the artificial cerebrospinal fluid traditionally contains relatively high concentrations of calcium (2-4 mM) to support synaptic transmission and suppress neuronal excitability. Using an ion-selective electrode, we determined the fraction of ionized calcium in healthy human cerebrospinal fluid to 1.0mM of a total concentration of 1.2 mM (86%). Using patch-clamp and extracellular recordings in the CA1 region in acute slices of rat hippocampus, we then compared the effects of this physiological concentration of calcium with the commonly used 2 mM on neuronal excitability, synaptic transmission, and long-term potentiation (LTP) to examine the magnitude of changes in this range of extracellular calcium. Increasing the total extracellular calcium concentration from 1.2 to 2 mM decreased spontaneous action potential firing, induced a depolarization of the threshold, and increased the rate of both de- and repolarization of the action potential. Evoked synaptic transmission was approximately doubled, with a balanced effect between inhibition and excitation. In 1.2mM calcium high-frequency stimulation did not result in any LTP, whereas a prominent LTP was observed at 2 or 4 mM calcium. Surprisingly, this inability to induce LTP persisted during blockade of GABAergic inhibition. In conclusion, an increase from the physiological 1.2 mM to 2 mM calcium in the artificial cerebrospinal fluid has striking effects on neuronal excitability, synaptic transmission, and the induction of LTP.
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| 23. |
- Groc, L., et al.
(författare)
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AMPA signalling in nascent glutamatergic synapses: there and not there!
- 2006
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Ingår i: Trends in neurosciences. - : Elsevier BV. - 0166-2236. ; 29:3, s. 132-9
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Forskningsöversikt (refereegranskat)abstract
- Nascent glutamatergic synapses are thought to be equipped with only NMDA receptors and to mature in a stepwise fashion when AMPA receptors are acquired later, through specific patterns of activity. We review recent data suggesting that AMPA receptors are in fact present in the nascent synapse but in a labile state. The nascent synapse can easily switch between AMPA-signalling and AMPA-silent states in a manner not requiring activation of NMDA receptors or metabotropic glutamate receptors. NMDA receptor activation by correlated presynaptic and postsynaptic activity can switch the nascent synapse to a mature, more stable state, in which AMPA receptor signalling is modified only through conventional plasticity processes. Thus, the AMPA receptor silence of nascent glutamatergic synapses depends on the synaptic activation history rather than on the nascent state itself.
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| 24. |
- Hanse, Eric, 1962, et al.
(författare)
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AMPA-silent synapses in brain development and pathology.
- 2013
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Ingår i: Nature reviews. Neuroscience. - : Springer Science and Business Media LLC. - 1471-0048 .- 1471-003X. ; 14:12, s. 839-50
-
Tidskriftsartikel (refereegranskat)abstract
- Synapses are constantly generated at a high rate in the developing, prepubescent brain. Newly generated glutamatergic synapses lack functional AMPA receptor-mediated transmission. Most of these 'AMPA-silent' synapses are eliminated during the developmental period, but some are specifically selected for AMPA unsilencing by correlated pre-and postsynaptic activity as the first step in a process that leads to stabilization of the synapse. Premature, or delayed, unsilencing of AMPA-silent synapses has been implicated in neurodevelopmental disorders, and abnormal generation of AMPA-silent synapses is associated with brain trauma, addiction and neurodegenerative disorders, further highlighting the importance of AMPA-silent synapses in brain pathology.
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| 25. |
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| 26. |
- Hanse, Eric, 1962, et al.
(författare)
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Glutamate synapse in developing brain: an integrative perspective beyond the silent state.
- 2009
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Ingår i: Trends in neurosciences. - : Elsevier BV. - 1878-108X .- 0166-2236. ; 32:10, s. 532-7
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Tidskriftsartikel (refereegranskat)abstract
- Cellular events underlying the establishment of glutamate transmission have been the focus of attention because appropriate wiring of developing neuronal networks is essential for adult brain functions. Although establishment of a synapse is a dynamic process requiring axonal and dendritic refinements, the functional interplay between pre- and postsynaptic signaling is often ignored. Here, we discuss recent data on pre- and postsynaptic plasticity of the glutamate synapse in the developing brain. The key aspect of the proposed model is that developing synapses are functionally labile in response to activity and this lability is counteracted by Hebbian activity. Both presynaptic and postsynaptic (loss of AMPA receptor signaling) mechanisms contribute to lability. Therefore, synapses in the developing brain maintain their capacity for functional AMPA signaling either by being presynaptically silent or by having participated in Hebbian activity; any synaptic activity outside this context leads instead to AMPA silencing and possible synaptic elimination.
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| 27. |
- Hanse, Eric, 1962, et al.
(författare)
-
[The medical education in Gothenburg is being reformed. Professional development, research and internationalization]
- 2011
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Ingår i: Läkartidningen. - 0023-7205. ; 108:12, s. 669-73
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Tidskriftsartikel (refereegranskat)abstract
- The medical education at the Sahlgrenska Academy, University of Gothenburg, is being reformed by an emphasis on professional development, international contacts and research. Students’ professional development consists of five core areas: Communication and self-reflection, Leadership and teamwork, Ethical attitude, Human rights and gender issues, and a Scientific and critical attitude. A learning progression of students’ professional competence is organised by five process leaders, coordinating core learning objectives and examinations within the existing curriculum. By promoting international exchange, more than half of the students in undergraduate medical education have had international contacts. The Sahlgrenska Academy aims to promote medical students’ interest for research and to increase the percentage among medical doctors that have a PhD degree. A program for combining medical education with research and teaching is being launched along with a MD/PhD program for medical basic science and a special PhD/MD program.
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| 28. |
- Innala, Marcus, et al.
(författare)
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3D Culturing and differentiation of SH-SY5Y neuroblastoma cells on bacterial nanocellulose scaffolds.
- 2014
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Ingår i: Artificial cells, nanomedicine, and biotechnology (Print). - : Informa UK Limited. - 2169-141X .- 2169-1401. ; 42:5, s. 302-308
-
Tidskriftsartikel (refereegranskat)abstract
- A new in vitro model, mimicking the complexity of nerve tissue, was developed based on a bacterial nanocellulose (BNC) scaffold that supports 3D culturing of neuronal cells. BNC is extracellularly excreted by Gluconacetobacter xylinus (G. xylinus) in the shape of long non-aggregated nanofibrils. The cellulose network created by G. xylinus has good mechanical properties, 99% water content, and the ability to be shaped into 3D structures by culturing in different molds. Surface modification with trimethyl ammonium beta-hydroxypropyl (TMAHP) to induce a positive surface charge, followed by collagen I coating, has been used to improve cell adhesion, growth, and differentiation on the scaffold. In the present study, we used SH-SY5Y neuroblastoma cells as a neuronal model. These cells attached and proliferated well on the BNC scaffold, as demonstrated by scanning electron microscopy (SEM) and the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay. Following neuronal differentiation, we demonstrated functional action potentials (APs) by electrophysiological recordings, indicating the presence of mature neurons on the scaffolds. In conclusion, we have demonstrated for the first time that neurons can attach, proliferate, and differentiate on BNC. This 3D model based on BNC scaffolds could possibly be used for developing in vitro disease models, when combined with human induced pluripotent stem (iPS) cells (derived from diseased patients) for detailed investigations of neurodegenerative disease mechanisms and in the search for new therapeutics.
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| 29. |
- Izsak, Julia, et al.
(författare)
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Robust generation of person-specific, synchronously active neuronal networks using purely isogenic human iPSC-3D neural aggregate cultures
- 2019
-
Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 13
-
Tidskriftsartikel (refereegranskat)abstract
- Reproducibly generating human induced pluripotent stem cell-based functional neuronal circuits, solely obtained from single individuals, poses particular challenges to achieve personalized and patient specific functional neuronal in vitro models. A hallmark of functional neuronal assemblies, synchronous neuronal activity, can be non-invasively studied by microelectrode array (MEA) technology, reliably capturing physiological and pathophysiological aspects of human brain function. In our here presented manuscript, we demonstrate a procedure to generate 3D neural aggregates comprising astrocytes, oligodendroglial cells, and neurons obtained from the same human tissue sample. Moreover, we demonstrate the robust ability of those neurons to create a highly synchronously active neuronal network within 3 weeks in vitro, without additionally applied astrocytes. The fusion of MEA-technology with functional neuronal circuits solely obtained from one individual's cells represent isogenic person-specific human neuronal sensor chips that pave the way for specific personalized in vitro neuronal networks as well as neurological and neuropsychiatric disease modeling.
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| 30. |
- Johannesson, S., et al.
(författare)
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Bacterial nanocellulose scaffolds; a novel three-dimensional in vitro model for neuronal cell culture
- 2012
-
Ingår i: Journal of Tissue Engineering and Regenerative Medicine. - 1932-6254 .- 1932-7005. ; 6:Suppl. 1
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterized by loss of synapses and neurons. To be able to achieve a deeper understanding of the mechanisms behind neurodegenerative diseases, advanced and reliable in vitro models, preferable based on human cells, are needed. This project focuses on the development of an in vitro artificial 3D neuronal network model based on neuronal cells seeded on nano-cellulose scaffold. The viability and maturity of the neuronal cells grown on the scaffolds have been evaluated using electron microscopy, immunohistochemical- and electrophysiological methods. We have investigated the possibility to use bacterial nanocellulose (BNC) as an extracellular matrix mimic for neural cell culture. To further enhance cell attachment on the BNC we used different chemical surface modifications (THMAP and CDAP-treatment) and protein coatings such as Collagen type 1. The human neuroblastoma cell line SH-SY5Y, was used as a neuronal cell model due to its ability to be differentiated into mature neurons. With electron microscopy the cells were visualized on the material, showing that the cells were well integrated with the BNC and showed good proliferation and viability. Whole cell patch clamp recordings showed that it is possible to differentiate the SH-SY5Y cells to mature neuronal cells on the BNC, as demonstrated with an ability of the cells to produce mature action potentials.
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| 31. |
- Kim, Malin, et al.
(författare)
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Antisecretory factor modulates GABAergic transmission in the rat hippocampus.
- 2005
-
Ingår i: Regulatory peptides. - : Elsevier BV. - 0167-0115. ; 129:1-3, s. 109-18
-
Tidskriftsartikel (refereegranskat)abstract
- Antisecretory Factor (AF) is a protein that has been implicated in the suppression of intestinal hypersecretion and inflammation. Intestinal secretion and inflammation are partly under local and central neural control raising the possibility that AF might exert its action by modulating neural signaling. In the present study we have investigated whether AF can modulate central synaptic transmission. Evoked glutamatergic and GABAergic synaptic transmissions were investigated using extracellular recordings in the CA1 region of hippocampal slices from adult rats. AF (0.5 microg/ml) suppressed GABA(A)-mediated synaptic transmission by about 40% while having no effect on glutamatergic transmission. Per oral administration of cholera toxin as well as feeding of rats with a diet containing hydrothermally processed cereals, known to upregulate endogenous AF plasma activity, mimicked the effect of exogenously administered AF on hippocampal GABAergic transmission. Our results identify AF as a neuromodulator and further raise the possibility that the hippocampus and AF are involved in a gut-brain loop controlling intestinal secretion and inflammation.
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| 32. |
- Kovalchuk, Yury, et al.
(författare)
-
Postsynaptic Induction of BDNF-Mediated Long-Term Potentiation.
- 2002
-
Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 295:5560, s. 1729-34
-
Tidskriftsartikel (refereegranskat)abstract
- Brain-derived neurotrophic factor (BDNF) and other neurotrophins are critically involved in long-term potentiation (LTP). Previous reports point to a presynaptic site of neurotrophin action. By imaging dentate granule cells in mouse hippocampal slices, we identified BDNF-evoked Ca2+ transients in dendrites and spines, but not at presynaptic sites. Pairing a weak burst of synaptic stimulation with a brief dendritic BDNF application caused an immediate and robust induction of LTP. LTP induction required activation of postsynaptic Ca2+ channels and N-methyl-d-aspartate receptors and was prevented by the blockage of postsynaptic Ca2+ transients. Thus, our results suggest that BDNF-mediated LTP is induced postsynaptically. Our finding that dendritic spines are the exclusive synaptic sites for rapid BDNF-evoked Ca2+ signaling supports this conclusion.
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| 33. |
- Lindgren, Stefan, et al.
(författare)
-
Medical education in Sweden
- 2011
-
Ingår i: Medical teacher. - London : Update. - 0142-159X .- 1466-187X. ; 33:10, s. 798-803
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Tidskriftsartikel (refereegranskat)abstract
- Undergraduate medical education in Sweden has moved from nationally regulated, subject-based courses to programmes integrated either around organ systems or physiological and patho-physiological processes, or organised around basic medical science in conjunction with clinical specialities, with individual profiles at the seven medical schools. The national regulations are restricted to overall academic and professional outcomes. The 51/2 year long university undergraduate curriculum is followed by a mandatory 18 months internship, delivered by the County Councils. While quality control and accreditation for the university curriculum is provided by the Swedish National Agency for Higher Education, no such formal control exists for the internship; undergraduate medical education is therefore in conflict with EU directives from 2005. The Government is expected to move towards 6 years long university undergraduate programmes, leading to licence, which will facilitate international mobility of both Swedish and foreign medical students and doctors. Ongoing academic development of undergraduate education is strengthened by the Bologna process. It includes outcome (competence)-based curricula, university Masters level complying with international standards, progression of competence throughout the curriculum, student directed learning, active participation and roles in practical clinical education and a national assessment model to assure professional competence. In the near future, the dimensioning of Swedish undergraduate education is likely to be decided more by international demands and aspects of quality than by national demands for doctors.
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| 34. |
- Ma, Rong, et al.
(författare)
-
Homosynaptic frequency-dependent depression by release site inactivation at neonatal hippocampal synapses in the stratum lacunosum-moleculare
- 2021
-
Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 54:3, s. 4838-4862
-
Tidskriftsartikel (refereegranskat)abstract
- When activated at low frequencies (0.1-1 Hz), second postnatal week synapses onto the most distal part of the apical dendritic tree (stratum lacunosum-moleculare) of rat hippocampal CA1 pyramidal cells display a frequency-dependent synaptic depression not observed for the more proximal (stratum radiatum) synapses. Depression in this frequency range is thought of as a possible contributor to behavioural habituation. In fact, in contrast to the proximal synapses, the distal synapses provide more direct sensory information from the entorhinal cortex as well as from thalamic nuclei. The use of antagonists showed that the activation of GABA(A), GABA(B), NMDA, mGlu, kainate, adenosine, or endocannabinoid receptors was not directly involved in the depression, indicating it to be intrinsic to the synapses themselves. While the depression affected paired-pulse plasticity in a manner indicating a decrease in vesicle release probability, the depression could not be explained by a stimulus-dependent decrease in calcium influx. Despite affecting the synaptic response evoked by brief high-frequency stimulation (10 impulses, 20 Hz) in a manner indicating vesicle depletion, the depression was unaffected by large variations in release probability. The depression was found not only to affect the synaptic transmission at low frequencies (0.1-1 Hz) but also to contribute to the depression evolving during brief high-frequency stimulation (10 impulses, 20 Hz). We propose that a release-independent process directly inactivating release sites with a fast onset (ms) and long duration (up to 20 s) underlies this synaptic depression.
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| 35. |
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| 36. |
- Magnelind, Per, 1975, et al.
(författare)
-
HTS SQUID measurements of evoked magnetic fields from transverse hippocampal slices : New Frontiers in Biomagnetism. Proceedings of the 15th International Conference on Biomagnetism, Vancouver, BC, Canada, August 21-25, 2006
- 2007
-
Ingår i: International Congress Series, New Frontiers in Biomagnetism. - : Elsevier BV. ; 1300, s. 578-581
-
Konferensbidrag (refereegranskat)abstract
- We have developed a high-transition-temperature superconducting quantum interference device system aimed at neuromagnetic measurements of evoked fields from in vitro brain slices. Recordings from transverse hippocampal slices from rat have been performed and they showed neuromagnetic fields of ∼ 5 pT
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| 37. |
- Magnelind, Per, 1975, et al.
(författare)
-
HTS SQUID measurements of evoked magnetic fields from transverse hippocampal slices
- 2007
-
Ingår i: International Congress Series, New Frontiers in Biomagnetism. - : Elsevier BV. - 0531-5131. ; 1300, s. 578-581
-
Konferensbidrag (refereegranskat)abstract
- We have developed a high-transition-temperature superconducting quantum interference device system aimed at neuromagnetic measurements of evoked fields from in vitro brain slices. Recordings from transverse hippocampal slices from rat have been performed and they showed neuromagnetic fields of ∼ 5 pT
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| 38. |
- Magnelind, P., et al.
(författare)
-
Magnetophysiology of brain slices using HTS SQUID magnetometer system
- 2009
-
Ingår i: Applications of Nonlinear Dynamics: Model and Design of Complex Systems. Series: Understanding Complex Systems. Eds.: In, Visarath; Longhini, Patrick; Palacios, Antonio. - : Springer. - 9783540856313 ; , s. 323-30
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 39. |
- Michaëlsson, Henrik, et al.
(författare)
-
The novel antidepressant ketamine enhances dentate gyrus proliferation with no effects on synaptic plasticity or hippocampal function in depressive-like rats
- 2019
-
Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 225:4
-
Tidskriftsartikel (refereegranskat)abstract
- Aim Major depressive disorder is a common and debilitating condition with substantial economic impact. Treatment options, although effective, are aimed at relieving the symptoms with limited disease modification. Ketamine, a commonly used anaesthetic, has received substantial attention as it shows rapid antidepressant effects clinically. We studied the effects of ketamine on hippocampal function and dentate gyrus proliferation in rats showing a depressive-like phenotype. Methods Adolescent and adult animals were pre-natally exposed to the glucocorticoid analog dexamethasone, and we verified a depressive-like phenotype using behavioural tests, such as the sucrose preference. We subsequently studied the effects of ketamine on hippocampal synaptic transmission, plasticity and dentate gyrus proliferation. In addition, we measured hippocampal glutamate receptor expression. We also tested the ketamine metabolite hydroxynorketamine for NMDA-receptor independent effects. Results Surprisingly, our extensive experimental survey revealed limited effects of ketamine or its metabolite on hippocampal function in control as well as depressive-like animals. We found no effects on synaptic efficacy or induction of long-term potentiation in adolescent and adult animals. Also there was no difference when comparing the dorsal and ventral hippocampus. Importantly, however, ketamine 24 hours prior to experimentation significantly increased the dentate gyrus proliferation, as revealed by Ki-67 immunostaining, in the depressive-like phenotype. Conclusion We find limited effects of ketamine on hippocampal glutamatergic transmission. Instead, alterations in dentate gyrus proliferation could explain the antidepressant effects of ketamine.
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| 40. |
- Perez-Alcazar, Marta, et al.
(författare)
-
Altered cognitive performance and synaptic function in the hippocampus of mice lacking C3.
- 2014
-
Ingår i: Experimental neurology. - : Elsevier BV. - 1090-2430 .- 0014-4886. ; 253C, s. 154-164
-
Tidskriftsartikel (refereegranskat)abstract
- Previous work implicated the complement system in adult neurogenesis as well as elimination of synapses in the developing and injured CNS. In the present study, we used mice lacking the third complement component (C3) to elucidate the role the complement system plays in hippocampus-dependent learning and synaptic function. We found that the constitutive absence of C3 is associated with enhanced place and reversal learning in adult mice. Our findings of lower release probability at CA3-CA1 glutamatergic synapses in combination with unaltered overall efficacy of these synapses in C3 deficient mice implicate C3 as a negative regulator of the number of functional glutamatergic synapses in the hippocampus. The C3 deficient mice showed no signs of spontaneous epileptiform activity in the hippocampus. We conclude that C3 plays a role in the regulation of the number and function of glutamatergic synapses in the hippocampus and exerts negative effects on hippocampus-dependent cognitive performance.
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| 41. |
- Perez-Alcazar, Marta, et al.
(författare)
-
Human Cerebrospinal Fluid Promotes Neuronal Viability and Activity of Hippocampal Neuronal Circuits In Vitro
- 2016
-
Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- For decades it has been hypothesized that molecules within the cerebrospinal fluid (CSF) diffuse into the brain parenchyma and influence the function of neurons. However, the functional consequences of CSF on neuronal circuits are largely unexplored and unknown. A major reason for this is the absence of appropriate neuronal in vitro model systems, and it is uncertain if neurons cultured in pure CSF survive and preserve electrophysiological functionality in vitro. In this article, we present an approach to address how human CSF (hCSF) influences neuronal circuits in vitro. We validate our approach by comparing the morphology, viability, and electrophysiological function of single neurons and at the network level in rat organotypic slice and primary neuronal cultures cultivated either in hCSF or in defined standard culture media. Our results demonstrate that rodent hippocampal slices and primary neurons cultured in hCSF maintain neuronal morphology and preserve synaptic transmission. Importantly, we show that hCSF increases neuronal viability and the number of electrophysiologically active neurons in comparison to the culture media. In summary, our data indicate that hCSF represents a physiological environment for neurons in vitro and a superior culture condition compared to the defined standard media. Moreover, this experimental approach paves the way to assess the functional consequences of CSF on neuronal circuits as well as suggesting a novel strategy for central nervous system (CNS) disease modeling.
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| 42. |
- Ponten, Henrik, et al.
(författare)
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Behavioral and neurochemical repercussions of hippocampal network activity blockade during the neonatal period.
- 2005
-
Ingår i: Brain research. Developmental brain research. - : Elsevier BV. - 0165-3806. ; 155:1, s. 81-6
-
Tidskriftsartikel (refereegranskat)abstract
- Early destruction of the ventral hippocampus from postnatal day 7 (P7) has been shown to induce behavioral alterations in post-pubertal rats, similar to those observed in models for schizophrenia. Using a single injection of tetanus toxin into the ventral hippocampus at P1, we tested the consequences of an early neonatal activity deprivation (
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| 43. |
- Portelius, Erik, 1977, et al.
(författare)
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Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease.
- 2010
-
Ingår i: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 5:2
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Alzheimer's disease (AD) is associated with deposition of amyloid beta (Abeta) in the brain, which is reflected by low concentration of the Abeta1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional Abeta peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of Abeta. Here, we test the hypothesis that AD is characterized by a specific CSF Abeta isoform pattern that is distinct when comparing sporadic AD (SAD) and familial AD (FAD) due to different mechanisms underlying brain amyloid pathology in the two disease groups. RESULTS: We measured Abeta isoform concentrations in CSF from 18 patients with SAD, 7 carriers of the FAD-associated presenilin 1 (PSEN1) A431E mutation, 17 healthy controls and 6 patients with depression using immunoprecipitation-mass spectrometry. Low CSF levels of Abeta1-42 and high levels of Abeta1-16 distinguished SAD patients and FAD mutation carriers from healthy controls and depressed patients. SAD and FAD were characterized by similar changes in Abeta1-42 and Abeta1-16, but FAD mutation carriers exhibited very low levels of Abeta1-37, Abeta1-38 and Abeta1-39. CONCLUSION: SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF Abeta isoform patterns that hold clinically relevant diagnostic information. PSEN1 A431E mutation carriers exhibit low levels of Abeta1-37, Abeta1-38 and Abeta1-39; fragments that are normally produced by gamma-secretase, suggesting that the PSEN1 A431E mutation modulates gamma-secretase cleavage site preference in a disease-promoting manner.
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| 44. |
- Riebe, Ilse, 1978, et al.
(författare)
-
Development of synaptic connectivity onto interneurons in stratum radiatum in the CA1 region of the rat hippocampus.
- 2012
-
Ingår i: BMC neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: The impact of a given presynaptic neuron on the firing probability of the postsynaptic neuron critically depends on the number of functional release sites that connect the two neurons. One way of determining the average functional synaptic connectivity onto a postsynaptic neuron is to compare the amplitudes of action potential dependent spontaneous synaptic currents with the amplitude of the synaptic currents that are independent of action potentials ("minis"). With this method it has been found that average synaptic connectivity between glutamatergic CA3 and CA1 pyramidal cells increases from single connections in the neonatal rat, to multiple connections in the young adult rat. On the other hand, gamma-aminobutyric acid (GABA)ergic interneurons form multiple connections onto CA1 pyramidal cells already in the neonatal rat, and the degree of multiple GABAergic connectivity is preserved into adulthood. In the present study, we have examined the development of glutamate and GABA connectivity onto GABAergic CA1 stratum radiatum interneurons in the hippocampal slice, and compared this to the connectivity onto CA1 pyramidal neurons. RESULTS: In GABAergic interneurons in the CA1 stratum radiatum, irrespective of developmental stage, we found that the average amplitude of action potential dependent spontaneous AMPA receptor-mediated synaptic currents were of the same magnitude as the mini AMPA receptor mediated synaptic currents. This finding indicates that these GABAergic interneurons, in contrast to the CA1 pyramidal neurons, preserve single glutamate connectivity throughout development. For GABA connectivity, on the other hand, we found multiple functional synaptic connections onto the interneurons, as onto the pyramidal cells. CONCLUSIONS: The results presented here confirm that glutamate and GABA synaptic connectivity develop very differently in the hippocampal CA1 region. Thus, whereas average GABA connectivity is multiple throughout the development, glutamate connectivity is unitary early in development. Our results further suggest that the development of glutamate synaptic connectivity differs markedly between pyramidal cells and GABAergic interneurons in stratum radiatum, such that a given presynaptic glutamatergic cell appears not allowed to increase its connectivity onto the postsynaptic stratum radiatum interneuron, as it may do onto the postsynaptic CA1 pyramidal cell.
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| 45. |
- Riebe, Ilse, 1978, et al.
(författare)
-
Silent synapses onto interneurons in the rat CA1 stratum radiatum.
- 2009
-
Ingår i: The European journal of neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 29:9, s. 1870-82
-
Tidskriftsartikel (refereegranskat)abstract
- Glutamate transmission to gamma-aminobutyric acid (GABA)ergic interneurons and to principal neurons differs in various important respects. Whether these differences exist from an early developmental stage, or result from differential development from a more common state, is unclear. In the hippocampal CA1 area, glutamate transmission to the developing, but not to the adult, principal neurons is characterized by the presence of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) silent synapses and of AMPA silencing induced by test pulse stimulation (0.03-1 Hz). In the present study, we examined whether this developmental difference in AMPA signaling is also true for glutamate transmission to CA1 stratum radiatum interneurons. We found that AMPA silent synapses onto these interneurons also exist, and that they can be generated by test pulse stimulation. In marked contrast to AMPA silencing in principal neurons, AMPA silencing in interneurons was not developmentally restricted, but was observed to the same extent after the first postnatal month as in the second postnatal week. In addition, we found that glutamate synapses onto these interneurons can also be N-methyl-d-aspartate (NMDA)-silent, that is, only AMPA-signaling. After test pulse stimulation, the AMPA-silent, the NMDA-silent and the AMPA/NMDA-signaling synapses onto the developing interneurons were estimated to be about equally frequent. These results highlight a diversity of glutamate signaling to CA1 stratum radiatum interneurons, and they indicate that the glutamate synapses onto pyramidal neurons and to interneurons can mature differentially.
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| 46. |
- Riebe, Ilse, 1978, et al.
(författare)
-
Tonically active NMDA receptors - a signalling mechanism critical for interneuronal excitability in the CA1 stratum radiatum.
- 2016
-
Ingår i: The European journal of neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 43:2, s. 169-178
-
Tidskriftsartikel (refereegranskat)abstract
- In contrast to tonic extrasynaptic GABAA receptor-mediated signalling, the physiological significance of tonic extrasynaptic NMDA receptor-mediated (NMDAR) signalling remains uncertain. In this study we used reversible open-channel blockers of NMDARs, memantine and phencyclidine (PCP), as tools to examine tonic NMDAR-mediated signalling in rat hippocampal slices. Memantine in concentrations up to 10 μM had no effect on synaptically evoked NMDAR-mediated responses in pyramidal neurons or GABAergic interneurons. On the other hand, 10 μM memantine reduced tonic NMDAR-mediated currents in GABAergic interneurons by approximately 50%. These tonic NMDAR-mediated currents in interneurons contributed significantly to the excitability of the interneurons since 10 μM memantine reduced the disynaptic IPSC in pyramidal cells by about 50%. Moreover, 10 μM memantine, but also PCP in concentrations ≤ 1 μM, increased the magnitude of the population spike, likely because of disinhibition. The relatively higher impact of tonic NMDAR-mediated signalling in interneurons was at least partly explained by the expression of GluN2D-containing NMDARs, which was not observed in mature pyramidal cells. Our results are consistent with the idea that low doses of readily reversible NMDA receptor open-channel blockers preferentially inhibits tonically active extrasynaptic NMDARs, and they suggest that tonically active NMDARs contribute more prominently to the intrinsic excitation in GABAergic interneurons than in pyramidal cells. We propose that this specific difference between interneurons and pyramidal cells can explain the disinhibition caused by the Alzheimer's disease medication memantine. This article is protected by copyright. All rights reserved.
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| 47. |
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| 48. |
- Strandberg, Joakim, 1978, et al.
(författare)
-
The endogenous peptide antisecretory factor promotes tonic GABAergic signaling in CA1 stratum radiatum interneurons
- 2014
-
Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Tonic GABAergic inhibition regulates neuronal excitability and has been implicated to be involved in both neurological and psychiatric diseases. We have previously shown that the endogenous peptide antisecretory factor (AF) decreases phasic GABAergic inhibition onto pyramidal CA1 neurons. In the present study, using whole-cell patch-clamp recordings, we investigated the mechanisms behind this disinhibition of CA1 pyramidal neurons by AF We found that application of AF to acute rat hippocampal slices resulted in a reduction of the frequency, but not of the amplitude, of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons. Miniature inhibitory postsynaptic currents (mIPSCs), recorded in the presence of tetrodotoxin (TTX), were however not affected by AF, neither in CA1 pyramidal cells, nor in stratum radiatum interneurons. Instead, AF caused an increase of the tonic GABA(A) current in stratum radiaturn intemeurons, leaving the tonic GABAergic transmission in CA1 pyramidal cells unaffected. These results show that the endogenous peptide AF enhances tonic, but not phasic, GABAergic signaling in CA1 stratum radiatum interneurons, without affecting tonic GABAergic signaling in CA1 pyramidal neurons. We suggest that this increased tonic GABAergic signaling in GABAergic interneurons could be a mechanism for the AF mediated disinhibition of pyramidal neurons.
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| 49. |
- Umek, T., et al.
(författare)
-
Oligonucleotides Targeting DNA Repeats Downregulate Huntingtin Gene Expression in Huntington's Patient-Derived Neural Model System
- 2021
-
Ingår i: Nucleic Acid Therapeutics. - : Mary Ann Liebert Inc. - 2159-3337 .- 2159-3345. ; 31:6, s. 443-456
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is one of the most common, dominantly inherited neurodegenerative disorders. It affects the striatum, cerebral cortex, and other subcortical structures leading to involuntary movement abnormalities, emotional disturbances, and cognitive impairments. HD is caused by a CAG center dot CTG trinucleotide-repeat expansion in exon 1 of the huntingtin (HTT) gene leading to the formation of mutant HTT (mtHTT) protein aggregates. Besides the toxicity of the mutated protein, there is also evidence that mtHTT transcripts contribute to the disease. Thus, the reduction of both mutated mRNA and protein would be most beneficial as a treatment. Previously, we designed a novel anti-gene oligonucleotide (AGO)-based strategy directly targeting the HTT trinucleotide-repeats in DNA and reported downregulation of mRNA and protein in HD patient fibroblasts. In this study, we differentiate HD patient-derived induced pluripotent stem cells to investigate the efficacy of the AGO, a DNA/Locked Nucleic Acid mixmer with phosphorothioate backbone, to modulate HTT transcription during neural in vitro development. For the first time, we demonstrate downregulation of HTT mRNA following both naked and magnetofected delivery into neural stem cells (NSCs) and show that neither emergence of neural rosette structures nor self-renewal of NSCs is compromised. Furthermore, the inhibition potency of both HTT mRNA and protein without off-target effects is confirmed in neurons. These results further validate an anti-gene approach for the treatment of HD.
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- Vizlin-Hodzic, Dzeneta, et al.
(författare)
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Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages
- 2017
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Neuro-inflammation and neuronal communication are considered as mis-regulated processes in the aetiology and pathology of bipolar disorder (BD). Which and when specific signal pathways become abnormal during the ontogeny of bipolar disorder patients is unknown. To address this question, we applied induced pluripotent stem cell (iPSC) technology followed by cortical neural differentiation on adipocyte-derived cells from BD type I patients (with psychotic episodes in psychiatric history) and healthy volunteers (controls). RNA sequencing in iPSC and cortical neural stem cell (NSC) lines were used to examine alterations between the transcriptomes from BD I and control samples during transition from the pluripotent stage towards the neural developmental stage. At the iPSC stage, the most highly significant differentially expressed gene (DEG) was the NLRP2 inflammasome (P = 2.66 × 10-10). Also among 42 DEGs at the NSC stage, NLRP2 showed the strongest statistical significance (P = 3.07 × 10-19). In addition, we have also identified several cytoskeleton-associated genes as DEGs from the NSC stage, such as TMP2, TAGLN, and ACTA2; the former two genes are recognised for the first time to be associated with BD. Our results also suggest that iPSC-derived BD-cortical NSCs carry several abnormalities in dopamine and GABA receptor canonical pathways, underlining that our in vitro BD model reflects pathology in the CNS. This would indicate that mis-regulated gene expression of inflammatory, neurotransmitter, and cytoskeletal signalling occurs during early foetal brain development of BD I patients.
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