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Abstract: Ectopic Neurogenesis Induced by Prenatal Antiepileptic Drug Exposure Augments Seizure Susceptibility in Adult Mice Sakai A, Matsuda T, Doi H, Nagaishi Y, Kato K, Nakashima K. Proc Natl Acad Sci U S A. 2018;115(16):4270-4275. Epilepsy is a neurological disorder often associated with seizure that affects ～0.7% of pregnant women. During pregnancy, most epileptic patients are prescribed antiepileptic drugs (AEDs) such as valproic acid (VPA) to control seizure activity. Here, we show that prenatal exposure to VPA in mice increases seizure susceptibility in adult offspring through mislocalization of newborn neurons in the hippocampus. We confirmed that neurons newly generated from neural stem/progenitor cells (NS/PCs) are integrated into the granular cell layer in the adult hippocampus; however, prenatal VPA treatment altered the expression in NS/PCs of genes associated with cell migration, including CXC motif chemokine receptor 4 (Cxcr4), consequently increasing the ectopic localization of newborn neurons in the hilus. We also found that voluntary exercise in a running wheel suppressed this ectopic neurogenesis and countered the enhanced seizure susceptibility caused by prenatal VPA exposure, probably by normalizing the VPA-disrupted expression of multiple genes including Cxcr4 in adult NS/PCs. Replenishing Cxcr4 expression alone in NS/PCs was sufficient to overcome the aberrant migration of newborn neurons and increased seizure susceptibility in VPA-exposed mice. Thus, prenatal exposure to an AED, VPA, has a long-term effect on the behavior of NS/PCs in offspring, but this effect can be counteracted by a simple physical activity. Our findings offer a step to developing strategies for managing detrimental effects in offspring exposed to VPA in utero.

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Double agent mTOR
Steve C. Danzer
- , 2019, DOI: 10.1177/1535759718822033

Abstract: Remodeled Cortical Inhibition Prevents Motor Seizures in Generalized Epilepsy Jiang X, Lupien-Meilleur A, Tazerart S, Lachance M, Samarova E, Araya R, Lacaille JC, Rossignol E. Ann Neurol. 2018 Sep;84(3):436-451. Objective: Deletions of CACNA1A, encoding the α1 subunit of CaV 2.1 channels, cause epilepsy with ataxia in humans. Whereas the deletion of Cacna1a in γ-aminobutyric acidergic (GABAergic) interneurons (INs) derived from the medial ganglionic eminence (MGE) impairs cortical inhibition and causes generalized seizures in Nkx2.1Cre;Cacna1ac/c mice, the targeted deletion of Cacna1a in somatostatin-expressing INs (SOM-INs), a subset of MGE-derived INs, does not result in seizures, indicating a crucial role of parvalbumin-expressing (PV) INs. Here, we identify the cellular and network consequences of Cacna1a deletion specifically in PV-INs. Methods: We generated PVCre;Cacna1ac/c mutant mice carrying a conditional Cacna1a deletion in PV neurons and evaluated the cortical cellular and network outcomes of this mutation by combining immunohistochemical assays, in vitro electrophysiology, 2-photon imaging, and in vivo video-electroencephalographic recordings. Results: PVCre;Cacna1ac/c mice display reduced cortical perisomatic inhibition and frequent absences, but only rare motor seizures. Compared to Nkx2.1Cre;Cacna1ac/c mice, PVCre;Cacna1ac/c mice have a net increase in cortical inhibition, with a gain of dendritic inhibition through sprouting of SOM-IN axons, largely preventing motor seizures. This beneficial compensatory remodeling of cortical GABAergic innervation is mechanistic target of rapamycin complex 1 (mTORC1)-dependent, and its inhibition with rapamycin leads to a striking increase in motor seizures. Furthermore, we show that a direct chemogenic activation of cortical SOM-INs prevents motor seizures in a model of kainate-induced seizures. Interpretation: Our findings provide novel evidence suggesting that the remodeling of cortical inhibition, with an mTOR-dependent gain of dendritic inhibition, determines the seizure phenotype in generalized epilepsy and that mTOR inhibition can be detrimental in epilepsies not primarily due to mTOR hyperactivation.

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Adult Neurogenesis in the Human Brain: Paradise Lost?
Steve C. Danzer
Epilepsy Currents , 2018, DOI: 10.5698/1535-7597.18.5.329

Abstract:

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Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation
Candi L. LaSarge,Steve C. Danzer
Frontiers in Molecular Neuroscience , 2014, DOI: 10.3389/fnmol.2014.00018

Abstract: The phosphatidylinositol-3-kinase/phosphatase and tensin homolog (PTEN)-mammalian target of rapamycin (mTOR) pathway regulates a variety of neuronal functions, including cell proliferation, survival, growth, and plasticity. Dysregulation of the pathway is implicated in the development of both genetic and acquired epilepsies. Indeed, several causal mutations have been identified in patients with epilepsy, the most prominent of these being mutations in PTEN and tuberous sclerosis complexes 1 and 2 (TSC1, TSC2). These genes act as negative regulators of mTOR signaling, and mutations lead to hyperactivation of the pathway. Animal models deleting PTEN, TSC1, and TSC2 consistently produce epilepsy phenotypes, demonstrating that increased mTOR signaling can provoke neuronal hyperexcitability. Given the broad range of changes induced by altered mTOR signaling, however, the mechanisms underlying seizure development in these animals remain uncertain. In transgenic mice, cell populations with hyperactive mTOR have many structural abnormalities that support recurrent circuit formation, including somatic and dendritic hypertrophy, aberrant basal dendrites, and enlargement of axon tracts. At the functional level, mTOR hyperactivation is commonly, but not always, associated with enhanced synaptic transmission and plasticity. Moreover, these populations of abnormal neurons can affect the larger network, inducing secondary changes that may explain paradoxical findings reported between cell and network functioning in different models or at different developmental time points. Here, we review the animal literature examining the link between mTOR hyperactivation and epileptogenesis, emphasizing the impact of enhanced mTOR signaling on neuronal form and function.

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Ablation of Newly Generated Hippocampal Granule Cells Has Disease-Modifying Effects in Epilepsy
Bethany E. Hosford,John P. Liska,Steve C. Danzer
- , 2016, DOI: 10.1523/JNEUROSCI.1371-16.2016

Abstract: Hippocampal granule cells generated in the weeks before and after an epileptogenic brain injury can integrate abnormally into the dentate gyrus, potentially mediating temporal lobe epileptogenesis. Previous studies have demonstrated that inhibiting granule cell production before an epileptogenic brain insult can mitigate epileptogenesis. Here, we extend upon these findings by ablating newly generated cells after the epileptogenic insult using a conditional, inducible diphtheria-toxin receptor expression strategy in mice. Diphtheria-toxin receptor expression was induced among granule cells born up to 5 weeks before pilocarpine-induced status epilepticus and these cells were then eliminated beginning 3 d after the epileptogenic injury. This treatment produced a 50% reduction in seizure frequency, but also a 20% increase in seizure duration, when the animals were examined 2 months later. These findings provide the first proof-of-concept data demonstrating that granule cell ablation therapy applied at a clinically relevant time point after injury can have disease-modifying effects in epilepsy. SIGNIFICANCE STATEMENT These findings support the long-standing hypothesis that newly generated dentate granule cells are pro-epileptogenic and contribute to the occurrence of seizures. This work also provides the first evidence that ablation of newly generated granule cells can be an effective therapy when begun at a clinically relevant time point after an epileptogenic insult. The present study also demonstrates that granule cell ablation, while reducing seizure frequency, paradoxically increases seizure duration. This paradoxical effect may reflect a disruption of homeostatic mechanisms that normally act to reduce seizure duration, but only when seizures occur frequently

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Impact of Corticosterone Treatment on Spontaneous Seizure Frequency and Epileptiform Activity in Mice with Chronic Epilepsy
Olagide W. Castro, Victor R. Santos, Raymund Y. K. Pun, Jessica M. McKlveen, Matthew Batie, Katherine D. Holland, Margaret Gardner, Norberto Garcia-Cairasco, James P. Herman, Steve C. Danzer
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046044

Abstract: Stress is the most commonly reported precipitating factor for seizures in patients with epilepsy. Despite compelling anecdotal evidence for stress-induced seizures, animal models of the phenomena are sparse and possible mechanisms are unclear. Here, we tested the hypothesis that increased levels of the stress-associated hormone corticosterone (CORT) would increase epileptiform activity and spontaneous seizure frequency in mice rendered epileptic following pilocarpine-induced status epilepticus. We monitored video-EEG activity in pilocarpine-treated mice 24/7 for a period of four or more weeks, during which animals were serially treated with CORT or vehicle. CORT increased the frequency and duration of epileptiform events within the first 24 hours of treatment, and this effect persisted for up to two weeks following termination of CORT injections. Interestingly, vehicle injection produced a transient spike in CORT levels – presumably due to the stress of injection – and a modest but significant increase in epileptiform activity. Neither CORT nor vehicle treatment significantly altered seizure frequency; although a small subset of animals did appear responsive. Taken together, our findings indicate that treatment of epileptic animals with exogenous CORT designed to mimic chronic stress can induce a persistent increase in interictal epileptiform activity.

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Differential Therapeutic Responses to DBT Skills Training and Validation: A Case Study [PDF]
Graham S. Danzer, Simon Ferber
Psychology (PSYCH) , 2014, DOI: 10.4236/psych.2014.57078

Abstract:

There is some debate in clinical circles about whether therapy should be oriented more to the client’s subjective emotional needs or to the client’s need for therapeutic direction and problem solving. Although not a true dichotomy, clinicians often orient more strongly to one of the aforementioned strategies or the other. Dialectical behavior therapy (DBT) offers a framework to practice both strategies, as it emphasizes both validation and skills training. It is hypothesized that either the validation, as an example of meeting client’s subjective emotional needs, or the skills training accounts for more of the therapeutic change in individuals with borderline personality disorder (BPD). This hypothesis is explored through the case of Teresa, a borderline client who received therapy that aligned with the principles of DBT. She seemed to respond most favorably to basic empathic connection and a subjective sense of being understood. Contrastingly, she tended to recoil from skills-focused interventions. Based on these results, limitations and implications for future research are proposed.

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Features of Traction Transformer Windings Utilised as Inductances
Jiri Danzer
Advances in Electrical and Electronic Engineering , 2004,

Abstract: The paper analyses features of traction transformer desing. Secondary windings of the transformer are utilized as a choke of an locomotive input filter at DC supplying system. Different ways of connections of the secondary windings coils are compared, reachable inductances are determined and forces affecting the coils are computed. The analysis is performed by FEM method for differend locomotive operating modes including breakdown service.

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Canonical fermion determinants in lattice QCD - Numerical evaluation and properties
Erek Bilgici,Julia Danzer,Christof Gattringer,C. B. Lang,Ludovit Liptak
Physics , 2009, DOI: 10.1016/j.physletb.2011.01.035

Abstract: We analyze canonical fermion determinants, i.e., fermion determinants projected to a fixed quark number q. The canonical determinants are computed using a dimensional reduction formula and are studied for pure SU(3) gauge configurations in a wide range of temperatures. It is demonstrated that the center sectors of the Polyakov loop very strongly manifest themselves in the behavior of the canonical determinants in the deconfined phase, and we discuss physical implications of this finding. Furthermore the distribution of the quark sectors is studied as a function of the temperature.

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