Publications by authors named "Kristina Lippmann"

9 Publications

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Post-stroke epileptogenesis is associated with altered intrinsic properties of hippocampal pyramidal neurons leading to increased theta resonance.

Neurobiol Dis 2021 Aug 10;156:105425. Epub 2021 Jun 10.

Grass Laboratory, Marine Biological Laboratory, Woods Hole, MA 02543, USA; Carl-Ludwig-Institute for Physiology, Medical Faculty, University of Leipzig, D-04103 Leipzig, Germany. Electronic address:

Brain insults like stroke, trauma or infections often lead to blood-brain barrier-dysfunction (BBBd) frequently resulting into epileptogenesis. Affected patients suffer from seizures and cognitive comorbidities that are potentially linked to altered network oscillations. It has been shown that a hippocampal BBBd in rats leads to in vivo seizures and increased power at theta (3-8 Hz), an important type of network oscillations. However, the underlying cellular mechanisms remain poorly understood. At membrane potentials close to the threshold for action potentials (APs) a subpopulation of CA1 pyramidal cells (PCs) displays intrinsic resonant properties due to an interplay of the muscarine-sensitive K-current (I) and the persistent Na-current (I). Such resonant neurons are more excitable and generate more APs when stimulated at theta frequencies, being strong candidates for contributing to hippocampal theta oscillations during epileptogenesis. We tested this hypothesis by characterizing changes in intrinsic properties of hippocampal PCs one week after post-stroke epileptogenesis, a model associated with BBBd, using slice electrophysiology and computer modeling. We find a higher proportion of resonant neurons in BBBd compared to sham animals (47 vs. 29%), accompanied by an increase in their excitability. In contrast, BBBd non-resonant neurons showed a reduced excitability, presented with lower impedance and more positive AP threshold. We identify an increase in I combined with either a reduction in I or an increase in I as possible mechanisms underlying the observed changes. Our results support the hypothesis that a higher proportion of more excitable resonant neurons in the hippocampus contributes to increased theta oscillations and an increased likelihood of seizures in a model of post-stroke epileptogenesis.
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http://dx.doi.org/10.1016/j.nbd.2021.105425DOI Listing
August 2021

Synaptic vesicles transiently dock to refill release sites.

Nat Neurosci 2020 11 28;23(11):1329-1338. Epub 2020 Sep 28.

Department of Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.

Synaptic vesicles fuse with the plasma membrane to release neurotransmitter following an action potential, after which new vesicles must 'dock' to refill vacated release sites. To capture synaptic vesicle exocytosis at cultured mouse hippocampal synapses, we induced single action potentials by electrical field stimulation, then subjected neurons to high-pressure freezing to examine their morphology by electron microscopy. During synchronous release, multiple vesicles can fuse at a single active zone. Fusions during synchronous release are distributed throughout the active zone, whereas fusions during asynchronous release are biased toward the center of the active zone. After stimulation, the total number of docked vesicles across all synapses decreases by ~40%. Within 14 ms, new vesicles are recruited and fully replenish the docked pool, but this docking is transient and they either undock or fuse within 100 ms. These results demonstrate that the recruitment of synaptic vesicles to release sites is rapid and reversible.
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http://dx.doi.org/10.1038/s41593-020-00716-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054220PMC
November 2020

Myosin VI Drives Clathrin-Mediated AMPA Receptor Endocytosis to Facilitate Cerebellar Long-Term Depression.

Cell Rep 2019 07;28(1):11-20.e9

Department of Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany. Electronic address:

Myosin VI is an actin-based cytoskeletal motor implicated in various steps of membrane trafficking. Here, we investigated whether this myosin is crucial for synaptic function and plasticity in neurons. We find that myosin VI localizes at cerebellar parallel fiber to Purkinje cell synapses and that the myosin is indispensable for long-term depression of AMPA-receptor-mediated synaptic signal transmission at this synapse. Moreover, direct visualization of GluA2-containing AMPA receptors in Purkinje cells reveals that the myosin drives removal of AMPA receptors from the surface of dendritic spines in an activity-dependent manner. Co-immunoprecipitation and super-resolution microscopy indicate that specifically the interaction of myosin VI with the clathrin adaptor component α-adaptin is important during long-term depression. Together, these data suggest that myosin VI directly promotes clathrin-mediated endocytosis of AMPA receptors in Purkinje cells to mediate cerebellar long-term depression. Our results provide insights into myosin VI function and the molecular mechanisms underlying synaptic plasticity.
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http://dx.doi.org/10.1016/j.celrep.2019.06.005DOI Listing
July 2019

TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults.

Sci Rep 2017 08 9;7(1):7711. Epub 2017 Aug 9.

Department of Integrative Biology, University of California Berkeley, Berkeley, CA, 94720, USA.

Brain damage due to stroke or traumatic brain injury (TBI), both leading causes of serious long-term disability, often leads to the development of epilepsy. Patients who develop post-injury epilepsy tend to have poor functional outcomes. Emerging evidence highlights a potential role for blood-brain barrier (BBB) dysfunction in the development of post-injury epilepsy. However, common mechanisms underlying the pathological hyperexcitability are largely unknown. Here, we show that comparative transcriptome analyses predict remodeling of extracellular matrix (ECM) as a common response to different types of injuries. ECM-related transcriptional changes were induced by the serum protein albumin via TGFβ signaling in primary astrocytes. In accordance with transcriptional responses, we found persistent degradation of protective ECM structures called perineuronal nets (PNNs) around fast-spiking inhibitory interneurons, in a rat model of TBI as well as in brains of human epileptic patients. Exposure of a naïve brain to albumin was sufficient to induce the transcriptional and translational upregulation of molecules related to ECM remodeling and the persistent breakdown of PNNs around fast-spiking inhibitory interneurons, which was contingent on TGFβ signaling activation. Our findings provide insights on how albumin extravasation that occurs upon BBB dysfunction in various brain injuries can predispose neural circuitry to the development of chronic inhibition deficits.
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http://dx.doi.org/10.1038/s41598-017-07394-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550510PMC
August 2017

Electrocorticographic Dynamics as a Novel Biomarker in Five Models of Epileptogenesis.

J Neurosci 2017 04 22;37(17):4450-4461. Epub 2017 Mar 22.

Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel,

Postinjury epilepsy (PIE) is a devastating sequela of various brain insults. While recent studies offer novel insights into the mechanisms underlying epileptogenesis and discover potential preventive treatments, the lack of PIE biomarkers hinders the clinical implementation of such treatments. Here we explored the biomarker potential of different electrographic features in five models of PIE. Electrocorticographic or intrahippocampal recordings of epileptogenesis (from the insult to the first spontaneous seizure) from two laboratories were analyzed in three mouse and two rat PIE models. Time, frequency, and fractal and nonlinear properties of the signals were examined, in addition to the daily rate of epileptiform spikes, the relative power of five frequency bands (theta, alpha, beta, low gamma, and high gamma) and the dynamics of these features over time. During the latent pre-seizure period, epileptiform spikes were more frequent in epileptic compared with nonepileptic rodents; however, this feature showed limited predictive power due to high inter- and intra-animal variability. While nondynamic rhythmic representation failed to predict epilepsy, the dynamics of the theta band were found to predict PIE with a sensitivity and specificity of >90%. Moreover, theta dynamics were found to be inversely correlated with the latency period (and thus predict the onset of seizures) and with the power change of the high-gamma rhythm. In addition, changes in theta band power during epileptogenesis were associated with altered locomotor activity and distorted circadian rhythm. These results suggest that changes in theta band during the epileptogenic period may serve as a diagnostic biomarker for epileptogenesis, able to predict the future onset of spontaneous seizures. Postinjury epilepsy is an unpreventable and devastating disorder that develops following brain injuries, such as traumatic brain injury and stroke, and is often associated with neuropsychiatric comorbidities. As PIE affects as many as 20% of brain-injured patients, reliable biomarkers are imperative before any preclinical therapeutics can find clinical translation. We demonstrate the capacity to predict the epileptic outcome in five different models of PIE, highlighting theta rhythm dynamics as a promising biomarker for epilepsy. Our findings prompt the exploration of theta dynamics (using repeated electroencephalographic recordings) as an epilepsy biomarker in brain injury patients.
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http://dx.doi.org/10.1523/JNEUROSCI.2446-16.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596657PMC
April 2017

Epileptiform activity and spreading depolarization in the blood-brain barrier-disrupted peri-infarct hippocampus are associated with impaired GABAergic inhibition and synaptic plasticity.

J Cereb Blood Flow Metab 2017 May 1;37(5):1803-1819. Epub 2016 Jan 1.

3 Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Peri-infarct opening of the blood-brain barrier may be associated with spreading depolarizations, seizures, and epileptogenesis as well as cognitive dysfunction. We aimed to investigate the mechanisms underlying neural network pathophysiology in the blood-brain barrier-dysfunctional hippocampus. Photothrombotic stroke within the rat neocortex was associated with increased intracranial pressure, vasogenic edema, and peri-ischemic blood-brain barrier dysfunction that included the ipsilateral hippocampus. Intrahippocampal recordings revealed electrographic seizures within the first week in two-thirds of animals, accompanied by a reduction in gamma and increase in theta frequency bands. Synaptic interactions were studied in parasagittal hippocampal slices at 24 h and seven days post-stroke. Field potential recordings in CA1 and CA3 uncovered multiple population spikes, epileptiform episodes, and spreading depolarizations at 24 h. Input-output analysis revealed that fEPSP-spike coupling was significantly enhanced at seven days. In addition, CA1 feedback and feedforward inhibition were diminished. Slices generating epileptiform activity at seven days revealed impaired bidirectional long-term plasticity following high and low-frequency stimulation protocols. Microarray and PCR data confirmed changes in expression of astrocyte-related genes and suggested downregulation in expression of GABA-receptor subunits. We conclude that blood-brain barrier dysfunction in the peri-infarct hippocampus is associated with early disinhibition, hyperexcitability, and abnormal synaptic plasticity.
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http://dx.doi.org/10.1177/0271678X16652631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435286PMC
May 2017

Synaptic plasticity in area CA1 of rat hippocampal slices following intraventricular application of albumin.

Neurobiol Dis 2016 07 10;91:155-65. Epub 2016 Mar 10.

Neuroscience Research Center and Institute of Neurophysiology, Charite-University Medicine Berlin, Berlin, Germany. Electronic address:

Epileptogenesis following insults to the brain may be triggered by a dysfunctional blood-brain barrier (BBB) associated with albumin extravasation and activation of astrocytes. Using ex vivo recordings from the BBB-disrupted hippocampus after neocortical photothrombotic stroke, we previously demonstrated abnormal activity-dependent accumulation of extracellular potassium with facilitated generation of seizure like events and spreading depolarizations. Similar changes could be observed after intracerebroventricular (icv) application of albumin. We hypothesized that alterations in extracellular potassium and glutamate homeostasis might lead to alterations in synaptic interactions. We therefore assessed the effects of icv albumin on homo- and heterosynaptic plasticity in hippocampal CA1, 24h after a single injection or 7days after continuous infusion of icv albumin. We demonstrate alterations in both homo- and heterosynaptic plasticity compared to control conditions in ex vivo slice studies. Albumin-treated tissue reveals (1) reduced long-term depression following low-frequency stimulation; (2) increased long-term potentiation of population spikes in response to 20Hz stimulation; (3) potentiated responses to Schaffer collateral stimulation following high-frequency stimulation of the direct cortical input and low-frequency stimulation of alveus and finally, (4) TGFβ receptor II (TGFβR-II) involvement in albumin-induced homosynaptic plasticity changes. We conclude that albumin-induced network hyperexcitability is associated with abnormal homo- and heterosynaptic plasticity that could partly be reversed by interference with TGFβR-II-mediated signaling and therefore it might be an important factor in the process of epileptogenesis.
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http://dx.doi.org/10.1016/j.nbd.2016.03.008DOI Listing
July 2016

Differential participation of pyramidal cells in generation of spontaneous sharp wave-ripples in the mouse subiculum in vitro.

Neurobiol Learn Mem 2015 Nov 28;125:113-9. Epub 2015 Aug 28.

Neuroscience Research Center and Institute of Neurophysiology, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. Electronic address:

Previously stored information in the hippocampus is believed to be replayed during sharp wave-ripple activity thereby serving transfer of information from hippocampal areas CA3 and CA1 to the cortical mantle and memory consolidation. The subiculum represents the main hippocampal output and contains both regular spiking and burst firing neurons that may project to different targets in the CNS. We recorded laminar profiles and intracellular correlates of spontaneous subicular events in mouse horizontal hippocampal slices and investigated involvement of the different subtypes of subicular pyramidal cells. Subicular sharp wave-ripples (SWRs) depend on input from the CA3 and CA1 regions as shown by microdissection experiments between hippocampal subareas. The extracellular subicular waves are associated with multiple unit activity, which varies in form and size. Intracellular recordings reveal that the same pyramidal cell can show different responses to SWRs. In the majority of cases, SWRs cause subthreshold depolarizing potentials. Burster neurons regularly contribute to generation of SWRs by action potential firing, whereas regular-spiking neurons are often inhibited.
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http://dx.doi.org/10.1016/j.nlm.2015.08.008DOI Listing
November 2015

Blood-brain barrier dysfunction can contribute to pharmacoresistance of seizures.

Epilepsia 2014 Aug 3;55(8):1255-63. Epub 2014 Jul 3.

Institute of Neurophysiology, Charite-University Medicine Berlin, Berlin, Germany.

Objective: We tested the hypothesis that interstitial albumin can contribute to pharmacoresistance, which is common among patients with focal epilepsies. These patients often present with an open blood-brain barrier (BBB), resulting in diffusion of drug-binding albumin into the brain interstitial space.

Methods: Seizure-like events (SLEs) induced by 100 μm 4-aminopyridine (4-AP) were monitored using extracellular field potential recordings from acute rat entorhinal cortex-hippocampus slices. Effects of standard antiepileptic drugs (phenytoin, valproic acid, carbamazepine, and phenobarbital) were studied in the presence of albumin applied acutely or by intraventricular injection. Unbound antiepileptic drugs (AEDs) were detected by ultrafiltration and high-performance liquid chromatography (HPLC).

Results: Contrary to the absence of albumin, conventional AEDs failed to suppress SLEs in the rat entorhinal cortex in the presence of albumin. This effect was partially caused by buffering of phenytoin and carbamazepine (CBZ) by albumin. Increasing CBZ concentration from 50 μm to 100 μm resulted in block of SLEs. In slices obtained from animals that were pretreated with intraventricular albumin application 24 h prior to experiment, CBZ suppressed SLEs similar to control slices. We also found that application of serum-like electrolytes transformed SLEs into late recurrent discharges (LRDs), which were no longer responding to CBZ.

Significance: A dysfunctional BBB with acute extravasation of serum albumin into the brain's interstitial space could contribute to pharmacoresistance. In such instances, choice of an AED with low albumin binding affinity may help in seizure control.
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http://dx.doi.org/10.1111/epi.12713DOI Listing
August 2014
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