| 1. |
- Woldbye, David P D, et al.
(författare)
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Differential suppression of seizures via Y2 and Y5 neuropeptide Y receptors.
- 2005
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 20:3, s. 760-772
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Tidskriftsartikel (refereegranskat)abstract
- Neuropepticle Y (NPY) prominently inhibits epileptic seizures in different animal models. The NPY receptors mediating this effect remain controversial partially due to lack of highly selective agonists and antagonists. To circumvent this problem, we used various NPY receptor knockout mice with the same genetic background and explored anti-epileptic action of NPY in vitro and in vivo. In Y2 (Y2-/-) and Y5 (Y5-/-) receptor knockouts, NPY partially inhibited 0 Mg2(+)-induced epileptiform activity in hippocampal slices. In contrast, in double knockouts (Y2Y5-/-), NPY had no effect, suggesting that in the hippocampus in vitro both receptors mediate anti-epileptiform action of NPY in an additive manner. Systemic kainate induced more severe seizures in Y5-/- and Y2Y5-/-, but not in Y2-/- mice, as compared to wild-type mice. Moreover, kainate seizures were aggravated by administration of the Y5 antagonist L-152,804 in wild-type mice. In Y5-/- mice, hippocampal kindling progressed faster, and afterdischarge durations were longer in amygdala, but not in hippocampus, as compared to wild-type controls. Taken together, these data suggest that, in mice, both Y2 and Y5 receptors regulate hippocampa seizures in vitro, while activation of Y5 receptors in extra-hippocampa: regions reduces generalized seizures in vivo.
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| 2. |
- Avaliani, Natalia, et al.
(författare)
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Optogenetics reveal delayed afferent synaptogenesis on grafted human induced pluripotent stem cell-derived neural progenitors.
- 2014
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 32:12, s. 3088-3098
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Tidskriftsartikel (refereegranskat)abstract
- Reprogramming of somatic cells into pluripotency stem cell state have opened new opportunities in cell replacement therapy and disease modeling in a number of neurological disorders. It still remains unknown, however, to what degree the grafted human induced pluripotent stem cells (hiPSCs) differentiate into a functional neuronal phenotype and if they integrate into the host circuitry. Here we present a detailed characterization of the functional properties and synaptic integration of hiPSC-derived neurons grafted in an in vitro model of hyperexcitable epileptic tissue, namely organotypic hippocampal slice cultures (OHSC), and in adult rats in vivo. The hiPSCs were first differentiated into long-term self-renewing neuroepithelial stem (lt-NES) cells, which are known to form primarily GABAergic neurons. When differentiated in OHSCs for six weeks, lt-NES cell-derived neurons displayed neuronal properties such as TTX-sensitive sodium currents and action potentials (APs), as well as both spontaneous and evoked postsynaptic currents, indicating functional afferent synaptic inputs. The grafted cells had a distinct electrophysiological profile compared to host cells in the OHSCs with higher input resistance, lower resting membrane potential and APs with lower amplitude and longer duration. To investigate the origin of synaptic afferents to the grafted lt-NES cell-derived neurons, the host neurons were transduced with Channelrhodopsin-2 (ChR2) and optogenetically activated by blue light. Simultaneous recordings of synaptic currents in grafted lt-NES cell-derived neurons using whole-cell patch-clamp technique at 6 weeks after grafting revealed limited synaptic connections from host neurons. Longer differentiation times, up to 24 weeks after grafting in vivo, revealed more mature intrinsic properties and extensive synaptic afferents from host neurons to the It-NES cell-derived neurons, suggesting that these cells require extended time for differentiation/maturation and synaptogenesis. However, even at this later time-point, the grafted cells maintained a higher input resistance. These data indicate that grafted lt-NES cell-derived neurons receive ample afferent input from the host brain. Since the lt-NES cells used in this study show a strong propensity for GABAergic differentiation, the host-to-graft synaptic afferents may facilitate inhibitory neurotransmitter release, and normalize hyperexcitable neuronal networks in brain diseases, e.g. such as epilepsy. Stem Cells 2014.
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| 3. |
- Benson, Thea Emily, et al.
(författare)
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Urinary bisphenol a, f and s levels and semen quality in young adult danish men
- 2021
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI AG. - 1661-7827 .- 1660-4601. ; 18:4
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Tidskriftsartikel (refereegranskat)abstract
- Bisphenol A (BPA) is considered an endocrine disruptor and has been associated with deleterious effects on spermatogenesis and male fertility. Bisphenol F (BPF) and S (BPS) are struc-turally similar to BPA, but knowledge of their effects on male fertility remains limited. In this cross– sectional study, we investigated the associations between exposure to BPA, BPF, and BPS and semen quality in 556 men 18–20 years of age from the Fetal Programming of Semen Quality (FEPOS) cohort. A urine sample was collected from each participant for determination of BPA, BPF, and BPS concentrations while a semen sample was collected to determine ejaculate volume, sperm concen-tration, total sperm count, sperm motility, and sperm morphology. Associations between urinary bisphenol levels (continuous and quartile–divided) and semen characteristics were estimated using a negative binomial regression model adjusting for urine creatinine concentration, alcohol intake, smoking status, body mass index (BMI), fever, sexual abstinence time, maternal pre–pregnancy BMI, and first trimester smoking, and highest parental education during first trimester. We found no associations between urinary bisphenol of semen quality in a sample of young men from the general Danish population.
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| 4. |
- Berglind, Fredrik, et al.
(författare)
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Neuronal activity dynamics in the dentate gyrus during early epileptogenesis
- 2023
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Ingår i: Epilepsy Research. - 0920-1211. ; 194
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Tidskriftsartikel (refereegranskat)abstract
- Epileptogenesis is a complex process involving a multitude of changes at the molecular, cellular and network level. Previous studies have identified several key alterations contributing to epileptogenesis and the development of hyper-excitability in different animal models, but only a few have focused on the early stages of this process. For post status epilepticus (SE) temporal lobe epilepsy in particular, understanding network dynamics during the early phases might be crucial for developing accurate preventive treatments to block the development of chronic spontaneous seizures. In this study, we used a viral vector mediated approach to examine activity of neurons in the dentate gyrus of the hippocampus during early epileptogenesis. We find that while granule cells are active 8 h after SE and then gradually decrease their activity, Calretinin-positive mossy cells and Neuropeptide Y-positive GABAergic interneurons in the hilus show a delayed activation pattern starting at 24 and peaking at 48 h after SE. These data suggest that indirect inhibition of granule cells by mossy cells through recruitment of local GABAergic interneurons could be an important mechanisms of excitability control during early epileptogenesis, and contribute to our understanding of the complex role of these cells in normal and pathological conditions.
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| 5. |
- Berglind, Fredrik, et al.
(författare)
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Optogenetic inhibition of chemically induced hypersynchronized bursting in mice.
- 2014
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 65, s. 133-141
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Tidskriftsartikel (refereegranskat)abstract
- Synchronized activity is common during various physiological operations but can culminate in seizures and consequently in epilepsy in pathological hyperexcitable conditions in the brain. Many types of seizures are not possible to control and impose significant disability for patients with epilepsy. Such intractable epilepsy cases are often associated with degeneration of inhibitory interneurons in the cortical areas resulting in impaired inhibitory drive onto the principal neurons. Recently emerging optogenetic technique has been proposed as an alternative approach to control such seizures but whether it may be effective in situations where inhibitory processes in the brain are compromised has not been addressed. Here we used pharmacological and optogenetic techniques to block inhibitory neurotransmission and induce epileptiform activity in vitro and in vivo. We demonstrate that NpHR-based optogenetic hyperpolarization and thereby inactivation of a principal neuronal population in the hippocampus is effectively attenuating seizure activity caused by disconnected network inhibition both in vitro and in vivo. Our data suggest that epileptiform activity in the hippocampus caused by impaired inhibition may be controlled by optogenetic silencing of principal neurons and potentially can be developed as an alternative treatment for epilepsy.
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| 6. |
- Gaml-Sørensen, Anne, et al.
(författare)
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Maternal vitamin D levels and male reproductive health : a population-based follow-up study
- 2023
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 38:5, s. 469-484
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Tidskriftsartikel (refereegranskat)abstract
- Maternal vitamin D levels during pregnancy may be important for reproductive health in male offspring by regulating cell proliferation and differentiation during development. We conducted a follow-up study of 827 young men from the Fetal Programming of Semen Quality (FEPOS) cohort, nested in the Danish National Birth Cohort to investigate if maternal vitamin D levels were associated with measures of reproductive health in adult sons. These included semen characteristics, testes volume, and reproductive hormone levels and were analysed according to maternal vitamin D (25(OH)D3) levels during pregnancy. In addition, an instrumental variable analysis using seasonality in sun exposure as an instrument for maternal vitamin D levels was conducted. We found that sons of mothers with vitamin D levels < 25 nmol/L had 11% (95% CI − 19 to − 2) lower testes volume and a 1.4 (95% CI 1.0 to 1.9) times higher risk of having low testes volume (< 15 mL), in addition to 20% (95% CI − 40 to 9) lower total sperm count and a 1.6 (95% CI 0.9 to 2.9) times higher risk of having a low total sperm count (< 39 million) compared with sons of mothers with vitamin D levels > 75 nmol/L. Continuous models, spline plots and an instrumental variable analysis supported these findings. Low maternal vitamin D levels were associated with lower testes volume and lower total sperm count with indications of dose-dependency. Maternal vitamin D level above 75 nmol/L during pregnancy may be beneficial for testes function in adult sons.
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| 7. |
- Gaml-Sørensen, Anne, et al.
(författare)
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The estimated effect of season and vitamin D in the first trimester on pubertal timing in girls and boys : A cohort study and an instrumental variable analysis
- 2023
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Ingår i: International Journal of Epidemiology. - 0300-5771. ; 52:5, s. 1328-1340
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Tidskriftsartikel (refereegranskat)abstract
- Background: Season of birth has been associated with age at menarche. Maternal vitamin D levels in pregnancy may explain this effect. We investigated whether the season of first trimester or maternal 25-hydroxyvitamin D3 [25(OH)D3] levels were associated with pubertal timing in children. Methods: We conducted a follow-up study of 15 819 children born in 2000-03 from the Puberty Cohort, nested in the Danish National Birth Cohort (DNBC). Mean differences in attaining numerous pubertal markers, including a combined estimate for the average age at attaining all pubertal markers, were estimated for low (November-April) relative to high (May-October) sunshine exposure season in the first trimester using multivariable interval-censored regression models. Moreover, we conducted a two-sample instrumental variable analysis using season as an instrument for maternal first-Trimester 25(OH)D3 plasma levels obtained from a non-overlapping subset (n = 827) in the DNBC. Results: For the combined estimate, girls and boys of mothers who had their first trimester during November-April had earlier pubertal timing than girls and boys of mothers whose first trimester occurred during May-October:-1.0 months (95% CI:-1.7 to-0.3) and-0.7 months (95% CI:-1.4 to-0.1), respectively. In the instrumental variable analysis, girls and boys also had earlier pubertal timing: respectively,-1.3 months (95% CI:-2.1 to-0.4) and-1.0 months (95% CI:-1.8 to-0.2) per SD (22 nmol/L) decrease in 25(OH)D3. Conclusions: Both first pregnancy trimester during November-April and lower 25(OH)D3 were associated with earlier pubertal timing in girls and boys.
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| 8. |
- Gotzsche, Casper R., et al.
(författare)
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Combined gene overexpression of neuropeptide Y and its receptor Y5 in the hippocampus suppresses seizures
- 2012
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 45:1, s. 288-296
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Tidskriftsartikel (refereegranskat)abstract
- We recently demonstrated that recombinant adeno-associated viral vector-induced hippocampal overexpression of neuropeptide Y receptor, Y2, exerts a seizure-suppressant effect in kindling and kainate-induced models of epilepsy in rats. Interestingly, additional overexpression of neuropeptide Y in the hippocampus strengthened the seizure-suppressant effect of transgene Y2 receptors. Here we show for the first time that another neuropeptide Y receptor, Y5, can also be overexpressed in the hippocampus. However, unlike Y2 receptor overexpression, transgene Y5 receptors in the hippocampus had no effect on kainate-induced motor seizures in rats. However, combined overexpression of Y5 receptors and neuropeptide Y exerted prominent suppression of seizures. This seizure-suppressant effect of combination gene therapy with Y5 receptors and neuropeptide Y was significantly stronger as compared to neuropeptide Y overexpression alone. These results suggest that overexpression of Y5 receptors in combination with neuropeptide Y could be an alternative approach for more effective suppression of hippocampal seizures. (C) 2011 Elsevier Inc. All rights reserved.
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| 9. |
- Kanter Schlifke, Irene, et al.
(författare)
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Galanin gene transfer curtails generalized seizures in kindled rats without altering hippocampal synaptic plasticity
- 2007
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Ingår i: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 150:4, s. 984-992
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Tidskriftsartikel (refereegranskat)abstract
- Gene therapy-based overexpression of endogenous seizure-suppressing molecules represents a promising treatment strategy for epilepsy. Viral vector-based overexpression of the neuropeptide galanin has been shown to effectively suppress generalized seizures in various animal models of epilepsy. However, it has not been explored whether such treatment can also prevent the epileptogenesis. Using a recombinant adeno-associated viral (rAAV) vector, we induced hippocampal galanin overexpression under the neuron specific enolase promoter in rats. Here we report that in animals with galanin overexpression, the duration of electrographic afterdischarges was shortened and initiation of convulsions was delayed at generalized seizure stages. However, the hippocampal kindling development was unchanged. Short-term plasticity of mossy fiber-cornu ammonis (CA) 3 synapses was unaltered, as assessed by paired-pulse and frequency facilitation of field excitatory postsynaptic potentials (fEPSPs) in hippocampal slices, suggesting that despite high transgene galanin expression, overall release probability of glutamate in these synapses was unaffected. These data indicate that hippocampal rAAV-based galanin overexpression is capable of mediating anticonvulsant effects by lowering the seizure susceptibility once generalized seizures are induced, but does not seem to affect kindling development or presynaptic short-term plasticity in mossy fibers.
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| 10. |
- Kokaia, Merab, et al.
(författare)
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Epilepsy and Gene Therapy: Resculpturing Synaptic Transmission with Neuropeptides
- 2009
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Ingår i: Encyclopedia of Basic Epilepsy Research. ; , s. 1430-1434
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Bokkapitel (refereegranskat)abstract
- One of the most promising and novel strategies to interfere with neurological disease processes is gene therapy using recombinant adeno-associated viral (rAAV) vectors. Such a rAAV-based gene delivery approach is rapidly advancing towards clinical trials. In this regard, neuropeptide Y (NPY) gene transduction into the brain tissue has attracted particular interest due to its potential to regulate and perhaps even ameliorate epileptic conditions. NPY gene transduction by viral vectors in epileptogenic regions of the brain can effectively suppress seizures in animals. The mechanisms underlying the seizure-suppressant effects of an NPY transgene are not well understood; in particular, under which circumstances transgene NPY is released, and whether and how it acts on synaptic transmission within the area of viral vector transduction are not known. These questions are of fundamental importance not only for the implementation of such a gene therapy approach in clinical trials with patients, but also for our general understanding of how transgene neuropeptides may act in the brain.
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