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Sökning: L773:0969 9961 OR L773:1095 953X > Kokaia Merab

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1.
  • Gloveli, T, et al. (författare)
  • Kindling alters entorhinal cortex-hippocampal interaction by increased efficacy of presynaptic GABA(B) autoreceptors in layer III of the entorhinal cortex
  • 2003
  • Ingår i: Neurobiology of Disease. - 0969-9961. ; 13:3, s. 203-212
  • Tidskriftsartikel (refereegranskat)abstract
    • We studied the effect of kindling, a model of temporal lobe epilepsy, on the frequency-dependent information transfer from the entorhinal cortex to the hippocampus in vitro. In control rats repetitive synaptic activation of layer III projection cells resulted in a frequency dependent depression of the synaptic transfer of action potentials to the hippocampus. One-to-two-days after kindling this effect was strongly reduced. Although no substantial change in synaptic inhibition upon single electrical stimulation was detected in kindled rats, there was a significant depression in the prolonged inhibition following high frequency stimulation. In kindled animals, paired-pulse depression (PPD) of stimulus-evoked IPSCs in layer III neurons was significantly stronger than in control rats. The increase of PPD is most likely caused by an increased presynaptic GABA(B) receptor-mediated autoinhibition. In kindled animals activation of presynaptic GABA(B) receptors by baclofen (10 muM) suppressed monosynaptic IPSCs significantly more than in control rats. In contrast, activation of postsynaptic GABA(B) receptors by baclofen was accompanied by comparable changes of the membrane conductance in both animal groups. Thus, in kindled animals activation of the layer III-CA1 pathway is facilitated by an increased GABA(B) receptor-mediated autoinhibition leading to an enhanced activation of the monosynaptic EC-CA1 pathway. (C) 2003 Elsevier Science (USA). All rights reserved.
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2.
  • Berglind, Fredrik, et al. (författare)
  • Optogenetic inhibition of chemically induced hypersynchronized bursting in mice.
  • 2014
  • Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 65, s. 133-141
  • 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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3.
  • Gotzsche, Casper R., et al. (författare)
  • Combined gene overexpression of neuropeptide Y and its receptor Y5 in the hippocampus suppresses seizures
  • 2012
  • Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 45:1, s. 288-296
  • 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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4.
  • Ledri, Marco, et al. (författare)
  • Optogenetics for controlling seizure circuits for translational approaches
  • 2023
  • Ingår i: Neurobiology of Disease. - 0969-9961. ; 184, s. 1-13
  • Tidskriftsartikel (refereegranskat)abstract
    • The advent of optogenetic tools has had a profound impact on modern neuroscience research, revolutionizing our understanding of the brain. These tools offer a remarkable ability to precisely manipulate specific groups of neurons with an unprecedented level of temporal precision, on the order of milliseconds. This breakthrough has significantly advanced our knowledge of various physiological and pathophysiological processes in the brain. Within the realm of epilepsy research, optogenetic tools have played a crucial role in investigating the contributions of different neuronal populations to the generation of seizures and hyperexcitability. By selectively activating or inhibiting specific neurons using optogenetics, researchers have been able to elucidate the underlying mechanisms and identify key players involved in epileptic activity. Moreover, optogenetic techniques have also been explored as innovative therapeutic strategies for treating epilepsy. These strategies aim to halt seizure progression and alleviate symptoms by utilizing the precise control offered by optogenetics. The application of optogenetic tools has provided valuable insights into the intricate workings of the brain during epileptic episodes. For instance, researchers have discovered how distinct interneuron populations contribute to the initiation of seizures (ictogenesis). They have also revealed how remote circuits in regions such as the cerebellum, septum, or raphe nuclei can interact with hyperexcitable networks in the hippocampus. Additionally, studies have demonstrated the potential of closed-loop systems, where optogenetics is combined with real-time monitoring, to enable precise, on-demand control of seizure activity. Despite the immense promise demonstrated by optogenetic approaches, it is important to acknowledge that many of these techniques are still in the early stages of development and have yet to reach potential clinical applications. The transition from experimental research to practical clinical use poses numerous challenges. In this review, we aim to introduce optogenetic tools, provide a comprehensive survey of their application in epilepsy research, and critically discuss their current potential and limitations in achieving successful clinical implementation for the treatment of human epilepsy. By addressing these crucial aspects, we hope to foster a deeper understanding of the current state and future prospects of optogenetics in epilepsy treatment.
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5.
  • Nikitidou, Litsa, et al. (författare)
  • Translational approach for gene therapy in epilepsy: Model system and unilateral overexpression of neuropeptide Y and Y2 receptors.
  • 2016
  • Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 86:nov 19, s. 52-61
  • Tidskriftsartikel (refereegranskat)abstract
    • Although novel treatment strategies based on the gene therapy approach for epilepsy has been encouraging, there is still a gap in demonstrating a proof-of-concept in a clinically relevant animal model and study design. In the present study, a conceptually novel framework reflecting a plausible clinical trial for gene therapy of temporal lobe epilepsy was explored: We investigated (i) whether the post intrahippocampal kainate-induced status epilepticus (SE) model of chronic epilepsy in rats could be clinically relevant; and (ii) whether a translationally designed neuropeptide Y (NPY)/Y2 receptor-based gene therapy approach targeting only the seizure-generating focus unilaterally can decrease seizure frequency in this chronic model of epilepsy. Our data suggest that the intrahippocampal kainate model resembles the disease development of human chronic mesial temporal lobe epilepsy (mTLE): (i) spontaneous seizures originate in the sclerotic hippocampus; (ii) only a part of the animals develops chronic epilepsy; (iii) animals show largely variable seizure frequency that (iv) tends to progressively increase over time. Despite significant hippocampal degeneration caused by kainate injection, the use of MRI allowed targeting the recombinant adeno-associated viral (rAAV) vectors encoding NPY and Y2 receptor genes to the remaining dorsal and ventral hippocampal areas ipsilateral to the kainate injection. Continuous video-EEG monitoring demonstrated not only prevention of the progressive increase in seizure frequency in rAAV-NPY/Y2 treated animals as compared to the controls, but even 45% decrease of seizure frequency in 80% of the epileptic animals. This translationally designed study in a clinically relevant model of epilepsy suggests that simultaneous overexpression of NPY and Y2 receptors unilaterally in the seizure focus is a relevant and promising approach that can be further validated in more extensive preclinical studies to develop a future treatment strategy for severe, often pharmacoresistant focal epilepsy cases that cannot be offered alternative therapeutic options.
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6.
  • Woldbye, David P D, et al. (författare)
  • Differential suppression of seizures via Y2 and Y5 neuropeptide Y receptors.
  • 2005
  • Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 20:3, s. 760-772
  • 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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