Publications by authors named "Heinz Beck"

88 Publications

Synchronous activity patterns in the dentate gyrus during immobility.

Elife 2021 Mar 12;10. Epub 2021 Mar 12.

Institute for Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.

The hippocampal dentate gyrus is an important relay conveying sensory information from the entorhinal cortex to the hippocampus proper. During exploration, the dentate gyrus has been proposed to act as a pattern separator. However, the dentate gyrus also shows structured activity during immobility and sleep. The properties of these activity patterns at cellular resolution, and their role in hippocampal-dependent memory processes have remained unclear. Using dual-color in vivo two-photon Ca imaging, we show that in immobile mice dentate granule cells generate sparse, synchronized activity patterns associated with entorhinal cortex activation. These population events are structured and modified by changes in the environment; and they incorporate place- and speed cells. Importantly, they are more similar than expected by chance to population patterns evoked during self-motion. Using optogenetic inhibition, we show that granule cell activity is not only required during exploration, but also during immobility in order to form dentate gyrus-dependent spatial memories.
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http://dx.doi.org/10.7554/eLife.65786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987346PMC
March 2021

Complex effects of eslicarbazepine on inhibitory micro networks in chronic experimental epilepsy.

Epilepsia 2021 02 16;62(2):542-556. Epub 2021 Jan 16.

Medical Faculty, Institute for Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.

Objective: Many antiseizure drugs (ASDs) act on voltage-dependent sodium channels, and the molecular basis of these effects is well established. In contrast, how ASDs act on the level of neuronal networks is much less understood.

Methods: In the present study, we determined the effects of eslicarbazepine (S-Lic) on different types of inhibitory neurons, as well as inhibitory motifs. Experiments were performed in hippocampal slices from both sham-control and chronically epileptic pilocarpine-treated rats.

Results: We found that S-Lic causes an unexpected reduction of feed-forward inhibition in the CA1 region at high concentrations (300 µM), but not at lower concentrations (100 µM). Concurrently, 300 but not 100 μM S-Lic significantly reduced maximal firing rates in putative feed-forward interneurons located in the CA1 stratum radiatum of sham-control and epileptic animals. In contrast, feedback inhibition was not inhibited by S-Lic. Instead, application of S-Lic, in contrast to previous data for other drugs like carbamazepine (CBZ), resulted in a lasting potentiation of feedback inhibitory post-synaptic currents (IPSCs) only in epileptic and not in sham-control animals, which persisted after washout of S-Lic. We hypothesized that this plasticity of inhibition might rely on anti-Hebbian potentiation of excitatory feedback inputs onto oriens-lacunosum moleculare (OLM) interneurons, which is dependent on Ca -permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Indeed, we show that blocking Ca -permeable AMPA receptors completely prevents upmodulation of feedback inhibition.

Significance: These results suggest that S-Lic affects inhibitory circuits in the CA1 hippocampal region in unexpected ways. In addition, ASD actions may not be sufficiently explained by acute effects on their target channels, rather, it may be necessary to take plasticity of inhibitory circuits into account.
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http://dx.doi.org/10.1111/epi.16808DOI Listing
February 2021

Nonspecific Expression in Limited Excitatory Cell Populations in Interneuron-Targeting Cre-driver Lines Can Have Large Functional Effects.

Front Neural Circuits 2020 27;14:16. Epub 2020 Apr 27.

Institute for Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.

Transgenic Cre-recombinase expressing mouse lines are widely used to express fluorescent proteins and opto-/chemogenetic actuators, making them a cornerstone of modern neuroscience. The investigation of interneurons in particular has benefitted from the ability to genetically target specific cell types. However, the specificity of some Cre driver lines has been called into question. Here, we show that nonspecific expression in a subset of hippocampal neurons can have substantial nonspecific functional effects in a somatostatin-Cre (SST-Cre) mouse line. Nonspecific targeting of CA3 pyramidal cells caused large optogenetically evoked excitatory currents in remote brain regions. Similar, but less severe patterns of nonspecific expression were observed in a widely used SST-IRES-Cre line, when crossed with a reporter mouse line. Viral transduction on the other hand yielded more specific expression but still resulted in nonspecific expression in a minority of pyramidal layer cells. These results suggest that a careful analysis of specificity is mandatory before the use of Cre driver lines for opto- or chemogenetic manipulation approaches.
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http://dx.doi.org/10.3389/fncir.2020.00016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197702PMC
April 2020

Quantitative properties of a feedback circuit predict frequency-dependent pattern separation.

Elife 2020 02 20;9. Epub 2020 Feb 20.

Institute for Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.

Feedback inhibitory motifs are thought to be important for pattern separation across species. How feedback circuits may implement pattern separation of biologically plausible, temporally structured input in mammals is, however, poorly understood. We have quantitatively determined key properties of feedback inhibition in the mouse dentate gyrus, a region critically involved in pattern separation. Feedback inhibition is recruited steeply with a low dynamic range (0% to 4% of active GCs), and with a non-uniform spatial profile. Additionally, net feedback inhibition shows frequency-dependent facilitation, driven by strongly facilitating mossy fiber inputs. Computational analyses show a significant contribution of the feedback circuit to pattern separation of theta modulated inputs, even within individual theta cycles. Moreover, pattern separation was selectively boosted at gamma frequencies, in particular for highly similar inputs. This effect was highly robust, suggesting that frequency-dependent pattern separation is a key feature of the feedback inhibitory microcircuit.
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http://dx.doi.org/10.7554/eLife.53148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032930PMC
February 2020

Altered Dynamics of Canonical Feedback Inhibition Predicts Increased Burst Transmission in Chronic Epilepsy.

J Neurosci 2019 11 13;39(45):8998-9012. Epub 2019 Sep 13.

Institute of Experimental Epileptology and Cognition Research, University of Bonn, 53105 Bonn, Germany,

Inhibitory interneurons, organized into canonical feedforward and feedback motifs, play a key role in controlling normal and pathological neuronal activity. We demonstrate prominent quantitative changes in the dynamics of feedback inhibition in a rat model of chronic epilepsy (male Wistar rats). Systematic interneuron recordings revealed a large decrease in intrinsic excitability of basket cells and oriens-lacunosum moleculare interneurons in epileptic animals. Additionally, the temporal dynamics of interneuron recruitment by recurrent feedback excitation were strongly altered, resulting in a profound loss of initial feedback inhibition during synchronous CA1 pyramidal activity. Biophysically constrained models of the complete feedback circuit motifs of normal and epileptic animals revealed that, as a consequence of altered feedback inhibition, burst activity arising in CA3 is more strongly converted to a CA1 output. This suggests that altered dynamics of feedback inhibition promote the transmission of epileptiform bursts to hippocampal projection areas. We quantitatively characterized changes of the CA1 feedback inhibitory circuit in a model of chronic temporal lobe epilepsy. This study shows, for the first time, that dynamic recruitment of inhibition in feedback circuits is altered and establishes the cellular mechanisms for this change. Computational modeling revealed that the observed changes are likely to systematically alter CA1 input-output properties leading to (1) increased seizure propagation through CA1 and (2) altered computation of synchronous CA3 input.
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http://dx.doi.org/10.1523/JNEUROSCI.2594-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832680PMC
November 2019

Partial sciatic nerve ligation leads to an upregulation of Ni-resistant T-type Ca currents in capsaicin-responsive nociceptive dorsal root ganglion neurons.

J Pain Res 2019 11;12:635-647. Epub 2019 Feb 11.

Department of Epileptology, University of Bonn Medical Center, Bonn, Germany,

Background: Neuropathic pain resulting from peripheral nerve lesions is a common medical condition, but current analgesics are often insufficient. The identification of key molecules involved in pathological pain processing is a prerequisite for the development of new analgesic drugs. Hyperexcitability of nociceptive DRG-neurons due to regulation of voltage-gated ion-channels is generally assumed to contribute strongly to neuropathic pain. There is increasing evidence, that T-type Ca-currents and in particular the Ca3.2 T-type-channel isoform play an important role in neuropathic pain, but experimental results are contradicting.

Purpose: To clarify the role of T-type Ca-channels and in particular the Ca3.2 T-type-channel isoform in neuropathic pain.

Methods: The effect of partial sciatic nerve ligation (PNL) on pain behavior and the properties of T-type-currents in nociceptive DRG-neurons was tested in wild-type and Ca3.2-deficient mice.

Results: In wild-type mice, PNL of the sciatic nerve caused neuropathic pain and an increase of T-type Ca-currents in capsaicin-responsive neurons, while capsaicin-unresponsive neurons were unaffected. Pharmacological experiments revealed that this upregulation was due to an increase of a Ni-resistant Ca-current component, inconsistent with Ca3.2 up-regulation. Moreover, following PNL Ca3.2-deficient mice showed neuropathic pain behavior and an increase of T-Type Ca-currents indistinguishable to that of PNL treated wild-type mice.

Conclusion: These data suggest that PNL induces an upregulation of T-Type Ca-currents in capsaicin-responsive DRG-neurons mediated by an increase of a Ni-insensitive current component (possibly Ca3.1 or Ca3.3). These findings provide relevance for the development of target specific analgesic drugs.
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http://dx.doi.org/10.2147/JPR.S138708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375107PMC
February 2019

Potassium channel-based optogenetic silencing.

Nat Commun 2018 11 5;9(1):4611. Epub 2018 Nov 5.

Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Neuroscience Research Center, 10117, Berlin, Germany.

Optogenetics enables manipulation of biological processes with light at high spatio-temporal resolution to control the behavior of cells, networks, or even whole animals. In contrast to the performance of excitatory rhodopsins, the effectiveness of inhibitory optogenetic tools is still insufficient. Here we report a two-component optical silencer system comprising photoactivated adenylyl cyclases (PACs) and the small cyclic nucleotide-gated potassium channel SthK. Activation of this 'PAC-K' silencer by brief pulses of low-intensity blue light causes robust and reversible silencing of cardiomyocyte excitation and neuronal firing. In vivo expression of PAC-K in mouse and zebrafish neurons is well tolerated, where blue light inhibits neuronal activity and blocks motor responses. In combination with red-light absorbing channelrhodopsins, the distinct action spectra of PACs allow independent bimodal control of neuronal activity. PAC-K represents a reliable optogenetic silencer with intrinsic amplification for sustained potassium-mediated hyperpolarization, conferring high operational light sensitivity to the cells of interest.
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http://dx.doi.org/10.1038/s41467-018-07038-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218482PMC
November 2018

A stably self-renewing adult blood-derived induced neural stem cell exhibiting patternability and epigenetic rejuvenation.

Nat Commun 2018 10 2;9(1):4047. Epub 2018 Oct 2.

Institute of Reconstructive Neurobiology, Life & Brain Center, University of Bonn Medical Center, 53127, Bonn, Germany.

Recent reports suggest that induced neurons (iNs), but not induced pluripotent stem cell (iPSC)-derived neurons, largely preserve age-associated traits. Here, we report on the extent of preserved epigenetic and transcriptional aging signatures in directly converted induced neural stem cells (iNSCs). Employing restricted and integration-free expression of SOX2 and c-MYC, we generated a fully functional, bona fide NSC population from adult blood cells that remains highly responsive to regional patterning cues. Upon conversion, low passage iNSCs display a profound loss of age-related DNA methylation signatures, which further erode across extended passaging, thereby approximating the DNA methylation age of isogenic iPSC-derived neural precursors. This epigenetic rejuvenation is accompanied by a lack of age-associated transcriptional signatures and absence of cellular aging hallmarks. We find iNSCs to be competent for modeling pathological protein aggregation and for neurotransplantation, depicting blood-to-NSC conversion as a rapid alternative route for both disease modeling and neuroregeneration.
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http://dx.doi.org/10.1038/s41467-018-06398-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168501PMC
October 2018

Effects of eslicarbazepine on slow inactivation processes of sodium channels in dentate gyrus granule cells.

Epilepsia 2018 08 28;59(8):1492-1506. Epub 2018 Jun 28.

Institute of Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.

Objective: Pharmacoresistance is a problem affecting ∼30% of chronic epilepsy patients. An understanding of the mechanisms of pharmacoresistance requires a precise understanding of how antiepileptic drugs interact with their targets in control and epileptic tissue. Although the effects of (S)-licarbazepine (S-Lic) on sodium channel fast inactivation are well understood and have revealed maintained activity in epileptic tissue, it is not known how slow inactivation processes are affected by S-Lic in epilepsy.

Methods: We have used voltage clamp recordings in isolated dentate granule cells (DGCs) and cortical pyramidal neurons of control versus chronically epileptic rats (pilocarpine model of epilepsy) and in DGCs isolated from hippocampal specimens from temporal lobe epilepsy patients to examine S-Lic effects on sodium channel slow inactivation.

Results: S-Lic effects on entry into and recovery from slow inactivation were negligible, even at high concentrations of S-Lic (300 μmol/L). Much more pronounced S-Lic effects were observed on the voltage dependence of slow inactivation, with significant effects at 100 μmol/L S-Lic in DGCs from control and epileptic rats or temporal lobe epilepsy patients. For none of these effects of S-Lic could we observe significant differences either between sham-control and epileptic rats, or between human DGCs and the two animal groups. S-Lic was similarly effective in cortical pyramidal neurons from sham-control and epileptic rats. Finally, we show in expression systems that S-Lic effects on slow inactivation voltage dependence are only observed in Na 1.2 and Na 1.6 subunits, but not in Na 1.1 and Na 1.3 subunits.

Significance: From these data, we conclude that a major mechanism of action of S-Lic is an effect on slow inactivation, primarily through effects on slow inactivation voltage dependence of Na 1.2 and Na 1.6 channels. Second, we demonstrate that this main effect of S-Lic is maintained in both experimental and human epilepsy and applies to principal neurons of different brain areas.
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http://dx.doi.org/10.1111/epi.14504DOI Listing
August 2018

Polyamine Modulation of Anticonvulsant Drug Response: A Potential Mechanism Contributing to Pharmacoresistance in Chronic Epilepsy.

J Neurosci 2018 06 22;38(24):5596-5605. Epub 2018 May 22.

Institute for Experimental Epileptology and Cognition Research,

Despite the development of numerous novel anticonvulsant drugs, ∼30% of epilepsy patients remain refractory to antiepileptic drugs (AEDs). Many established and novel AEDs reduce hyperexcitability via voltage- and use-dependent inhibition of voltage-gated Na channels. For the widely used anticonvulsant carbamazepine (CBZ), use-dependent block of Na channels is significantly reduced both in experimental and human epilepsy. However, the molecular underpinnings of this potential cellular mechanism for pharmacoresistance have remained enigmatic.Here, we describe the mechanism that leads to the emergence of CBZ-resistant Na channels. We focused on the endogenous polyamine system, which powerfully modulates Na channels in a use-dependent manner. We had shown previously that the intracellular polyamine spermine is reduced in chronic epilepsy, resulting in increased persistent Na currents. Because spermine and CBZ both bind use-dependently in spatial proximity within the Na channel pore, we hypothesized that spermine loss might also be related to diminished CBZ response. Using the pilocarpine model of refractory epilepsy in male rats and whole-cell patch-clamp recordings, we first replicated the reduction of use-dependent block by CBZ in chronically epileptic animals. We then substituted intracellular spermine via the patch pipette in different concentrations. Under these conditions, we found that exogenous spermine significantly rescues use-dependent block of Na channels by CBZ. These findings indicate that an unexpected modulatory mechanism, depletion of intracellular polyamines, leads both to increased persistent Na currents and to diminished CBZ sensitivity of Na channels. These findings could lead to novel strategies for overcoming pharmacoresistant epilepsy that target the polyamine system. Pharmacoresistant epilepsy affects ∼18 million people worldwide, and intense efforts have therefore been undertaken to uncover the underlying molecular and cellular mechanisms. One of the key known candidate mechanisms of pharmacoresistance has been a loss of use-dependent Na channel block by the anticonvulsant carbamazepine (CBZ), both in human and experimental epilepsies. Despite intense scrutiny, the molecular mechanisms underlying this phenomenon have not been elucidated. We now show that a loss of intracellular spermine in chronic epilepsy is a major causative factor leading to the development of CBZ-resistant Na currents. This finding can be exploited both for the screening of anticonvulsants in expression systems, and for novel strategies to overcome pharmacoresistance that target the polyamine system.
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http://dx.doi.org/10.1523/JNEUROSCI.0640-18.2018DOI Listing
June 2018

The Circuit Motif as a Conceptual Tool for Multilevel Neuroscience.

Trends Neurosci 2018 03;41(3):128-136

Institute for Experimental Epileptology and Cognition Research, Department of Epileptology, University of Bonn Medical Center, 53105 Bonn, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen, 53105 Bonn, Germany.

Modern neuroscientific techniques that specifically manipulate and measure neuronal activity in behaving animals now allow bridging of the gap from the cellular to the behavioral level. However, in doing so, they also pose new challenges. Research using incompletely defined manipulations in a high-dimensional space without clear hypotheses is likely to suffer from multiple well-known conceptual and statistical problems. In this context it is essential to develop hypotheses with testable implications across levels. Here we propose that a focus on circuit motifs can help achieve this goal. Viewing neural structures as an assembly of circuit motif building blocks is not new. However, recent tool advances have made it possible to extensively map, specifically manipulate, and quantitatively investigate circuit motifs and thereby reexamine their relevance to brain function.
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http://dx.doi.org/10.1016/j.tins.2018.01.002DOI Listing
March 2018

New developments in understanding focal cortical malformations.

Curr Opin Neurol 2018 04;31(2):151-155

Institute for Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.

Purpose Of Review: Focal cortical dysplasias (FCDs) represent common cortical malformations that are frequently associated with epilepsy. They have so far not been well understood in terms of their molecular pathogenesis, and with respect to mechanisms of seizure emergence.

Recent Findings: Several recent studies have succeeded in making significant advances in understanding the molecular genetics, in particular FCD type II. A second major advance has been the development of novel rodent models of FCDs that replicate a somatic mutation seen in humans, lead to a focal lesion, and recapitulate many phenotypic features of human FCDs. We will discuss these recent advances.

Summary: These advances promise significant advances in understanding the heterogeneity of FCDs at the molecular genetic level. They also promise a much better understanding of cell-intrinsic and network mechanisms underlying increased seizure susceptibility and altered cognition. Systematic studies utilizing the approaches summarized here promise to lead to specific strategies regarding when and how to treat specific subgroups of FCDs.
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http://dx.doi.org/10.1097/WCO.0000000000000531DOI Listing
April 2018

Neuropathic pain in experimental autoimmune neuritis is associated with altered electrophysiological properties of nociceptive DRG neurons.

Exp Neurol 2017 11 19;297:25-35. Epub 2017 Jul 19.

Department of Neurology, University of Bonn Medical Center, Sigmund Freud Straße 25, 53105 Bonn, Germany; Department of Epileptology, University of Bonn Medical Center, Sigmund Freud Straße 25, 53105 Bonn, Germany. Electronic address:

Guillain-Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy characterized by rapidly progressive paresis and sensory disturbances. Moderate to severe and often intractable neuropathic pain is a common symptom of GBS, but its underlying mechanisms are unknown. Pathology of GBS is classically attributed to demyelination of large, myelinated peripheral fibers. However, there is increasing evidence that neuropathic pain in GBS is associated with impaired function of small, unmyelinated, nociceptive fibers. We therefore examined the functional properties of small DRG neurons, the somata of nociceptive fibers, in a rat model of GBS (experimental autoimmune neuritis=EAN). EAN rats developed behavioral signs of neuropathic pain. This was accompanied by a significant shortening of action potentials due to a more rapid repolarization and an increase in repetitive firing in a subgroup of capsaicin-responsive DRG neurons. Na current measurements revealed a significant increase of the fast TTX-sensitive current and a reduction of the persistent TTX-sensitive current component. These changes of Na currents may account for the significant decrease in AP duration leading to an overall increase in excitability and are therefore possibly directly linked to pathological pain behavior. Thus, like in other animal models of neuropathic and inflammatory pain, Na channels seem to be crucially involved in the pathology of GBS and may constitute promising targets for pain modulating pharmaceuticals.
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http://dx.doi.org/10.1016/j.expneurol.2017.07.011DOI Listing
November 2017

Functional properties of granule cells with hilar basal dendrites in the epileptic dentate gyrus.

Epilepsia 2017 01 26;58(1):160-171. Epub 2016 Nov 26.

Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology, University of Bonn, Bonn, Germany.

Objective: The maturation of adult-born granule cells and their functional integration into the network is thought to play a key role in the proper functioning of the dentate gyrus. In temporal lobe epilepsy, adult-born granule cells in the dentate gyrus develop abnormally and possess a hilar basal dendrite (HBD). Although morphological studies have shown that these HBDs have synapses, little is known about the functional properties of these HBDs or the intrinsic and network properties of the granule cells that possess these aberrant dendrites.

Methods: We performed patch-clamp recordings of granule cells within the granule cell layer "normotopic" from sham-control and status epilepticus (SE) animals. Normotopic granule cells from SE animals possessed an HBD (SE HBD cells) or not (SE HBD cells). Apical and basal dendrites were stimulated using multiphoton uncaging of glutamate. Two-photon Ca imaging was used to measure Ca transients associated with back-propagating action potentials (bAPs).

Results: Near-synchronous synaptic input integrated linearly in apical dendrites from sham-control animals and was not significantly different in apical dendrites of SE HBD cells. The majority of HBDs integrated input linearly, similar to apical dendrites. However, 2 of 11 HBDs were capable of supralinear integration mediated by a dendritic spike. Furthermore, the bAP-evoked Ca transients were relatively well maintained along HBDs, compared with apical dendrites. This further suggests an enhanced electrogenesis in HBDs. In addition, the output of granule cells from epileptic tissue was enhanced, with both SE HBD and SE HBD cells displaying increased high-frequency (>100 Hz) burst-firing. Finally, both SE HBD and SE HBD cells received recurrent excitatory input that was capable of generating APs, especially in the absence of feedback inhibition.

Significance: Taken together, these data suggest that the enhanced excitability of HBDs combined with the altered intrinsic and network properties of granule cells collude to promote excitability and synchrony in the epileptic dentate gyrus.
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http://dx.doi.org/10.1111/epi.13605DOI Listing
January 2017

Activity of the anticonvulsant lacosamide in experimental and human epilepsy via selective effects on slow Na channel inactivation.

Epilepsia 2017 01 19;58(1):27-41. Epub 2016 Nov 19.

Department of Epileptology, Laboratory for Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.

Objective: In human epilepsy, pharmacoresistance to antiepileptic drug therapy is a major problem affecting ~30% of patients with epilepsy. Many classical antiepileptic drugs target voltage-gated sodium channels, and their potent activity in inhibiting high-frequency firing has been attributed to their strong use-dependent blocking action. In chronic epilepsy, a loss of use-dependent block has emerged as a potential cellular mechanism of pharmacoresistance for anticonvulsants acting on voltage-gated sodium channels. The anticonvulsant drug lacosamide (LCM) also targets sodium channels, but has been shown to preferentially affect sodium channel slow inactivation processes, in contrast to most other anticonvulsants.

Methods: We used whole-cell voltage clamp recordings in acutely isolated cells to investigate the effects of LCM on transient Na currents. Furthermore, we used whole-cell current clamp recordings to assess effects on repetitive action potential firing in hippocampal slices.

Results: We show here that LCM exerts its effects primarily via shifting the slow inactivation voltage dependence to more hyperpolarized potentials in hippocampal dentate granule cells from control and epileptic rats, and from patients with epilepsy. It is important to note that this activity of LCM was maintained in chronic experimental and human epilepsy. Furthermore, we demonstrate that the efficacy of LCM in inhibiting high-frequency firing is undiminished in chronic experimental and human epilepsy.

Significance: Taken together, these results show that LCM exhibits maintained efficacy in chronic epilepsy, in contrast to conventional use-dependent sodium channel blockers such as carbamazepine. They also establish that targeting slow inactivation may be a promising strategy for overcoming target mechanisms of pharmacoresistance.
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http://dx.doi.org/10.1111/epi.13602DOI Listing
January 2017

Burst firing of single neurons in the human medial temporal lobe changes before epileptic seizures.

Clin Neurophysiol 2016 10 20;127(10):3329-34. Epub 2016 Aug 20.

Cognitive and Clinical Neurophysiology, Department of Epileptology, University of Bonn, Bonn, Germany. Electronic address:

Objective: To better understand the mechanisms that lead to the sudden and unexpected occurrence of seizures, with the neuronal correlate being abnormally synchronous discharges that disrupt neuronal function.

Methods: To address this problem, we recorded single neuron activity in epilepsy patients during the transition to seizures to uncover specific changes of neuronal firing patterns. We focused particularly on neurons repeatedly firing discrete groups of high-frequency action potentials (so called bursters) that have been associated with ictogenesis. We analyzed a total of 459 single neurons and used the mean autocorrelation time as a quantitative measure of burstiness. To unravel the intricate roles of excitation and inhibition, we also examined differential contributions from putative principal cells and interneurons.

Results: During interictal recordings, burstiness was significantly higher in the seizure onset hemisphere, an effect found only for principal cells, but not for interneurons, and which disappeared before seizures.

Conclusion: These findings deviate from conventional views of ictogenesis that propose slowly-increasing aggregates of bursting neurons which give rise to seizures once they reach a critical mass.

Significance: Instead our results are in line with recent hypotheses that bursting may represent a protective mechanism by preventing direct transmission of postsynaptic high-frequency oscillations.
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http://dx.doi.org/10.1016/j.clinph.2016.08.010DOI Listing
October 2016

Advances in the development of biomarkers for epilepsy.

Lancet Neurol 2016 07;15(8):843-856

Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. Electronic address:

Over 50 million people worldwide have epilepsy. In nearly 30% of these cases, epilepsy remains unsatisfactorily controlled despite the availability of over 20 antiepileptic drugs. Moreover, no treatments exist to prevent the development of epilepsy in those at risk, despite an increasing understanding of the underlying molecular and cellular pathways. One of the major factors that have impeded rapid progress in these areas is the complex and multifactorial nature of epilepsy, and its heterogeneity. Therefore, the vision of developing targeted treatments for epilepsy relies upon the development of biomarkers that allow individually tailored treatment. Biomarkers for epilepsy typically fall into two broad categories: diagnostic biomarkers, which provide information on the clinical status of, and potentially the sensitivity to, specific treatments, and prognostic biomarkers, which allow prediction of future clinical features, such as the speed of progression, severity of epilepsy, development of comorbidities, or prediction of remission or cure. Prognostic biomarkers are of particular importance because they could be used to identify which patients will develop epilepsy and which might benefit from preventive treatments. Biomarker research faces several challenges; however, biomarkers could substantially improve the management of people with epilepsy and could lead to prevention in the right person at the right time, rather than just symptomatic treatment.
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http://dx.doi.org/10.1016/S1474-4422(16)00112-5DOI Listing
July 2016

Astrocyte Intermediaries of Septal Cholinergic Modulation in the Hippocampus.

Neuron 2016 05 5;90(4):853-65. Epub 2016 May 5.

Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. Electronic address:

The neurotransmitter acetylcholine, derived from the medial septum/diagonal band of Broca complex, has been accorded an important role in hippocampal learning and memory processes. However, the precise mechanisms whereby acetylcholine released from septohippocampal cholinergic neurons acts to modulate hippocampal microcircuits remain unknown. Here, we show that acetylcholine release from cholinergic septohippocampal projections causes a long-lasting GABAergic inhibition of hippocampal dentate granule cells in vivo and in vitro. This inhibition is caused by cholinergic activation of hilar astrocytes, which provide glutamatergic excitation of hilar inhibitory interneurons. These results demonstrate that acetylcholine release can cause slow inhibition of principal neuronal activity via astrocyte intermediaries.
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http://dx.doi.org/10.1016/j.neuron.2016.04.003DOI Listing
May 2016

Downregulation of Spermine Augments Dendritic Persistent Sodium Currents and Synaptic Integration after Status Epilepticus.

J Neurosci 2015 Nov;35(46):15240-53

Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology, and Deutsches Zentrum für Neurodegenerative Erkrankungen e.V., 53175 Bonn, Germany

Unlabelled: Dendritic voltage-gated ion channels profoundly shape the integrative properties of neuronal dendrites. In epilepsy, numerous changes in dendritic ion channels have been described, all of them due to either their altered transcription or phosphorylation. In pilocarpine-treated chronically epileptic rats, we describe a novel mechanism that causes an increased proximal dendritic persistent Na(+) current (INaP). We demonstrate using a combination of electrophysiology and molecular approaches that the upregulation of dendritic INaP is due to a relief from polyamine-dependent inhibition. The polyamine deficit in hippocampal neurons is likely caused by an upregulation of the degrading enzyme spermidine/spermine acetyltransferase. Multiphoton glutamate uncaging experiments revealed that the increase in dendritic INaP causes augmented dendritic summation of excitatory inputs. These results establish a novel post-transcriptional modification of ion channels in chronic epilepsy and may provide a novel avenue for treatment of temporal lobe epilepsy.

Significance Statement: In this paper, we describe a novel mechanism that causes increased dendritic persistent Na(+) current. We demonstrate using a combination of electrophysiology and molecular approaches that the upregulation of persistent Na(+) currents is due to a relief from polyamine-dependent inhibition. The polyamine deficit in hippocampal neurons is likely caused by an upregulation of the degrading enzyme spermidine/spermine acetyltransferase. Multiphoton glutamate uncaging experiments revealed that the increase in dendritic persistent Na current causes augmented dendritic summation of excitatory inputs. We believe that these results establish a novel post-transcriptional modification of ion channels in chronic epilepsy.
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http://dx.doi.org/10.1523/JNEUROSCI.0493-15.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605494PMC
November 2015

Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1.

Nat Commun 2015 Oct 26;6:8688. Epub 2015 Oct 26.

Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, Bonn 53105, Germany.

Temporal lobe epilepsy (TLE) is the most common focal seizure disorder in adults. In many patients, transient brain insults, including status epilepticus (SE), are followed by a latent period of epileptogenesis, preceding the emergence of clinical seizures. In experimental animals, transcriptional upregulation of CaV3.2 T-type Ca(2+)-channels, resulting in an increased propensity for burst discharges of hippocampal neurons, is an important trigger for epileptogenesis. Here we provide evidence that the metal-regulatory transcription factor 1 (MTF1) mediates the increase of CaV3.2 mRNA and intrinsic excitability consequent to a rise in intracellular Zn(2+) that is associated with SE. Adeno-associated viral (rAAV) transfer of MTF1 into murine hippocampi leads to increased CaV3.2 mRNA. Conversely, rAAV-mediated expression of a dominant-negative MTF1 abolishes SE-induced CaV3.2 mRNA upregulation and attenuates epileptogenesis. Finally, data from resected human hippocampi surgically treated for pharmacoresistant TLE support the Zn(2+)-MTF1-CaV3.2 cascade, thus providing new vistas for preventing and treating TLE.
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http://dx.doi.org/10.1038/ncomms9688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846312PMC
October 2015

Serum from a Patient with GAD65 Antibody-Associated Limbic Encephalitis Did Not Alter GABAergic Neurotransmission in Cultured Hippocampal Networks.

Front Neurol 2015 28;6:189. Epub 2015 Aug 28.

Department of Epileptology, University Hospital Bonn , Bonn , Germany ; Center for Rare Diseases Bonn (ZSEB), University Hospital Bonn , Bonn , Germany.

Background: Glutamate decarboxylase is an intracellular enzyme converting glutamate into GABA. Antibodies (abs) to its isoform GAD65 were described in limbic encephalitis and other neurological conditions. The significance of GAD65 abs for epilepsy is unclear, but alterations of inhibitory GABAergic neurotransmission may be involved. Here, we investigated the effects of the serum of a female patient suffering from GAD65 ab-associated LE on GABAA currents in cultured hippocampal networks.

Methods: Spontaneous or evoked post-synaptic GABAA currents were measured in cultured hippocampal neurons prepared from embryonic mice after 11-21 days in vitro using the patch-clamp technique in the whole-cell mode after incubation with serum of a healthy control or the LE-patient at a final concentration of 1% for 5-8 h.

Results: Properties of miniature inhibitory post-synaptic currents were not different in cultures treated with control and LE-serum. Likewise, paired-pulse ratio of evoked GABAA currents as a measure of release probability was not different in both conditions. Evoked GABAA currents were significantly depressed during 10 Hz stimulation without significant differences between control and LE-serum treated cultures.

Conclusion: In our experimental paradigms, serum of a patient with confirmed GAD65 ab-associated LE had no apparent effect on GABAergic neurotransmission in murine-cultured hippocampal networks. These results challenge the view that the presence of GAD65 abs invariably compromise inhibitory network function.
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http://dx.doi.org/10.3389/fneur.2015.00189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551833PMC
September 2015

Synergy of direct and indirect cholinergic septo-hippocampal pathways coordinates firing in hippocampal networks.

J Neurosci 2015 Jun;35(22):8394-410

Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology, Deutsches Zentrum für Neurodegenerative Erkrankungen, 53105 Bonn, Germany

The medial septum/diagonal band of Broca complex (MSDB) is a key structure that modulates hippocampal rhythmogenesis. Cholinergic neurons of the MSDB play a central role in generating and pacing theta-band oscillations in the hippocampal formation during exploration, novelty detection, and memory encoding. How precisely cholinergic neurons affect hippocampal network dynamics in vivo, however, has remained elusive. In this study, we show that stimulation of cholinergic MSDB neurons in urethane-anesthetized mice acts on hippocampal networks via two distinct pathways. A direct septo-hippocampal cholinergic projection causes increased firing of hippocampal inhibitory interneurons with concomitantly decreased firing of principal cells. In addition, cholinergic neurons recruit noncholinergic neurons within the MSDB. This indirect pathway is required for hippocampal theta synchronization. Activation of both pathways causes a reduction in pyramidal neuron firing and a more precise coupling to the theta oscillatory phase. These two anatomically and functionally distinct pathways are likely relevant for cholinergic control of encoding versus retrieval modes in the hippocampus.
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http://dx.doi.org/10.1523/JNEUROSCI.4460-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605336PMC
June 2015

Function and developmental origin of a mesocortical inhibitory circuit.

Nat Neurosci 2015 Jun 11;18(6):872-82. Epub 2015 May 11.

Neurodevelopmental Genetics, Institute of Reconstructive Neurobiology, Life and Brain Center, University of Bonn, Bonn, Germany.

Midbrain ventral tegmental neurons project to the prefrontal cortex and modulate cognitive functions. Using viral tracing, optogenetics and electrophysiology, we found that mesocortical neurons in the mouse ventrotegmental area provide fast glutamatergic excitation of GABAergic interneurons in the prefrontal cortex and inhibit prefrontal cortical pyramidal neurons in a robust and reliable manner. These mesocortical neurons were derived from a subset of dopaminergic progenitors, which were dependent on prolonged Sonic Hedgehog signaling for their induction. Loss of these progenitors resulted in the loss of the mesocortical inhibitory circuit and an increase in perseverative behavior, whereas mesolimbic and mesostriatal dopaminergic projections, as well as impulsivity and attentional function, were largely spared. Thus, we identified a previously uncharacterized mesocortical circuit contributing to perseverative behaviors and found that the diversity of dopaminergic neurons begins to be established during their progenitor phase.
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http://dx.doi.org/10.1038/nn.4020DOI Listing
June 2015

Selective aptamer-based control of intraneuronal signaling.

Angew Chem Int Ed Engl 2015 Apr 5;54(18):5369-73. Epub 2015 Mar 5.

Life and Medical Sciences Institute, University of Bonn, Gerhard-Domagk-Str. 1, Bonn (Germany).

Cellular behavior is orchestrated by the complex interactions of a myriad of intracellular signal transduction pathways. To understand and investigate the role of individual components in such signaling networks, the availability of specific inhibitors is of paramount importance. We report the generation and validation of a novel variant of an RNA aptamer that selectively inhibits the mitogen-activated kinase pathway in neurons. We demonstrate that the aptamer retains function under intracellular conditions and that application of the aptamer through the patch-clamp pipette efficiently inhibits mitogen-activated kinase-dependent synaptic plasticity. This approach introduces synthetic aptamers as generic tools, readily applicable to inhibit different components of intraneuronal signaling networks with utmost specificity.
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http://dx.doi.org/10.1002/anie.201409597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324602PMC
April 2015

Targeting pharmacoresistant epilepsy and epileptogenesis with a dual-purpose antiepileptic drug.

Brain 2015 Feb 2;138(Pt 2):371-87. Epub 2014 Dec 2.

1 Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology, University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany 5 German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany

In human epilepsy, pharmacoresistance to antiepileptic drug therapy is a major problem affecting a substantial fraction of patients. Many of the currently available antiepileptic drugs target voltage-gated sodium channels, leading to a rate-dependent suppression of neuronal discharge. A loss of use-dependent block has emerged as a potential cellular mechanism of pharmacoresistance for anticonvulsants acting on voltage-gated sodium channels. There is a need both for compounds that overcome this resistance mechanism and for novel drugs that inhibit the process of epileptogenesis. We show that eslicarbazepine acetate, a once-daily antiepileptic drug, may constitute a candidate compound that addresses both issues. Eslicarbazepine acetate is converted extensively to eslicarbazepine after oral administration. We have first tested using patch-clamp recording in human and rat hippocampal slices if eslicarbazepine, the major active metabolite of eslicarbazepine acetate, shows maintained activity in chronically epileptic tissue. We show that eslicarbazepine exhibits maintained use-dependent blocking effects both in human and experimental epilepsy with significant add-on effects to carbamazepine in human epilepsy. Second, we show that eslicarbazepine acetate also inhibits Cav3.2 T-type Ca(2+) channels, which have been shown to be key mediators of epileptogenesis. We then examined if transitory administration of eslicarbazepine acetate (once daily for 6 weeks, 150 mg/kg or 300 mg/kg) after induction of epilepsy in mice has an effect on the development of chronic seizures and neuropathological correlates of chronic epilepsy. We found that eslicarbazepine acetate exhibits strong antiepileptogenic effects in experimental epilepsy. EEG monitoring showed that transitory eslicarbazepine acetate treatment resulted in a significant decrease in seizure activity at the chronic state, 8 weeks after the end of treatment. Moreover, eslicarbazepine acetate treatment resulted in a significant decrease in mossy fibre sprouting into the inner molecular layer of pilocarpine-injected mice, as detected by Timm staining. In addition, epileptic animals treated with 150 mg/kg, but not those that received 300 mg/kg eslicarbazepine acetate showed an attenuated neuronal loss. These results indicate that eslicarbazepine potentially overcomes a cellular resistance mechanism to conventional antiepileptic drugs and at the same time constitutes a potent antiepileptogenic agent.
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http://dx.doi.org/10.1093/brain/awu339DOI Listing
February 2015

Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation.

J Neurosci 2014 Nov;34(45):14874-89

Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany,

Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na(+) channels in interneurons and persistent Na(+) currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca(2+) imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation.
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http://dx.doi.org/10.1523/JNEUROSCI.0721-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220023PMC
November 2014

Axon-carrying dendrites convey privileged synaptic input in hippocampal neurons.

Neuron 2014 Sep 4;83(6):1418-30. Epub 2014 Sep 4.

Institute of Physiology and Pathophysiology, Heidelberg University, 69120 Heidelberg, Germany; Bernstein Center for Computational Neuroscience (BCCN) Heidelberg/Mannheim, 69120 Heidelberg, Germany. Electronic address:

Neuronal processing is classically conceptualized as dendritic input, somatic integration, and axonal output. The axon initial segment, the proposed site of action potential generation, usually emanates directly from the soma. However, we found that axons of hippocampal pyramidal cells frequently derive from a basal dendrite rather than from the soma. This morphology is particularly enriched in central CA1, the principal hippocampal output area. Multiphoton glutamate uncaging revealed that input onto the axon-carrying dendrites (AcDs) was more efficient in eliciting action potential output than input onto regular basal dendrites. First, synaptic input onto AcDs generates action potentials with lower activation thresholds compared with regular dendrites. Second, AcDs are intrinsically more excitable, generating dendritic spikes with higher probability and greater strength. Thus, axon-carrying dendrites constitute a privileged channel for excitatory synaptic input in a subset of cortical pyramidal cells.
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http://dx.doi.org/10.1016/j.neuron.2014.08.013DOI Listing
September 2014

Function of inhibitory micronetworks is spared by Na+ channel-acting anticonvulsant drugs.

J Neurosci 2014 Jul;34(29):9720-35

Laboratory for Experimental Epileptology and Cognition Research and Department of Epileptology, University of Bonn, 53127 Bonn, Germany, Deutsches Zentrum für Neurodegenerative Erkrankungen e.V., 53175 Bonn, Germany,

The mechanisms of action of many CNS drugs have been studied extensively on the level of their target proteins, but the effects of these compounds on the level of complex CNS networks that are composed of different types of excitatory and inhibitory neurons are not well understood. Many currently used anticonvulsant drugs are known to exert potent use-dependent blocking effects on voltage-gated Na(+) channels, which are thought to underlie the inhibition of pathological high-frequency firing. However, some GABAergic inhibitory neurons are capable of firing at very high rates, suggesting that these anticonvulsants should cause impaired GABAergic inhibition. We have, therefore, studied the effects of anticonvulsant drugs acting via use-dependent block of voltage-gated Na(+) channels on GABAergic inhibitory micronetworks in the rodent hippocampus. We find that firing of pyramidal neurons is reliably inhibited in a use-dependent manner by the prototypical Na(+) channel blocker carbamazepine. In contrast, a combination of intrinsic and synaptic properties renders synaptically driven firing of interneurons essentially insensitive to this anticonvulsant. In addition, a combination of voltage imaging and electrophysiological experiments reveal that GABAergic feedforward and feedback inhibition is unaffected by carbamazepine and additional commonly used Na(+) channel-acting anticonvulsants, both in control and epileptic animals. Moreover, inhibition in control and epileptic rats recruited by in vivo activity patterns was similarly unaffected. These results suggest that sparing of inhibition is an important principle underlying the powerful reduction of CNS excitability exerted by anticonvulsant drugs.
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http://dx.doi.org/10.1523/JNEUROSCI.2395-13.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608323PMC
July 2014

The effects of eslicarbazepine on persistent Na⁺ current and the role of the Na⁺ channel β subunits.

Epilepsy Res 2014 Feb 8;108(2):202-11. Epub 2013 Dec 8.

University of Bonn, Department of Epileptology, Laboratory for Experimental Epileptology and Cognition Research, Bonn, Germany; University of Bonn, Department of Neurology, Bonn, Germany.

Eslicarbazepine is the major active metabolite of eslicarbazepine acetate, a once-daily antiepileptic drug approved in Europe as adjunctive therapy for refractory partial-onset seizures in adults. This study was aimed to determine the effects of eslicarbazepine on persistent Na(+) currents (INaP) and the role of β subunits in modulating these effects. To study the role of β subunits of the Na(+) channel we used a mouse line genetically lacking either the β1 or β2 subunit, encoded by the SCN1B or SCN2B gene, respectively. Whole cell patch-clamp recordings were performed on CA1 neurons in hippocampal slices under control conditions and application of 300 μM eslicarbazepine. We examined INaP in acutely isolated CA1 neurons and repetitive firing in hippocampal slices of mice lacking β subunits and corresponding wild-type littermates. We found that eslicarbazepine caused a significant reduction of maximal INaP conductance and an efficient reduction of the firing rate in wild-type mice. We have shown previously a paradoxical increase of conductance of INaP caused by carbamazepine in mice lacking β1 subunits in the subthreshold range, leading to a failure in affecting neuronal firing (Uebachs et al., 2010). In contrast, eslicarbazepine did not cause this paradoxical effect on INaP in SCN1B null mice. Consequently, the effects of eslicarbazepine on repetitive firing were maintained in these animals. These results indicate that eslicarbazepine exerts effects on INaP similar to those known for carbamazepine. However, in animals lacking the β1 Na(+) channel subunit these effects are maintained. Therefore, eslicarbazepine potentially overcomes a previously described putative mechanism of resistance to established Na(+) channel acting antiepileptic drugs.
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http://dx.doi.org/10.1016/j.eplepsyres.2013.11.022DOI Listing
February 2014

Impaired D-serine-mediated cotransmission mediates cognitive dysfunction in epilepsy.

J Neurosci 2013 Aug;33(32):13066-80

Laboratory of Experimental Epileptology, Department of Epileptology and Institute of Molecular Psychiatry, University of Bonn, D-53127 Bonn, Germany.

The modulation of synaptic plasticity by NMDA receptor (NMDAR)-mediated processes is essential for many forms of learning and memory. Activation of NMDARs by glutamate requires the binding of a coagonist to a regulatory site of the receptor. In many forebrain regions, this coagonist is d-serine. Here, we show that experimental epilepsy in rats is associated with a reduction in the CNS levels of d-serine, which leads to a desaturation of the coagonist binding site of synaptic and extrasynaptic NMDARs. In addition, the subunit composition of synaptic NMDARs changes in chronic epilepsy. The desaturation of NMDARs causes a deficit in hippocampal long-term potentiation, which can be rescued with exogenously supplied d-serine. Importantly, exogenous d-serine improves spatial learning in epileptic animals. These results strongly suggest that d-serine deficiency is important in the amnestic symptoms of temporal lobe epilepsy. Our results point to a possible clinical utility of d-serine to alleviate these disease manifestations.
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http://dx.doi.org/10.1523/JNEUROSCI.5423-12.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619718PMC
August 2013