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

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

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

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

Veränderte Netzwerk-Oszillationen und synaptische Plastizität stehen im Blut- Hirn-Schranken-gestörten peri-infarkt Hippocampus in Verbindung mit epileptiformer Aktivität und beeinträchtigter GABAerger Inhibition

Aquired epilepsies in the elderly often result from brain lesions associated with bloodbrain barrier (BBB)-disruption like stroke, trauma, tumors or brain infections. Post-stroke epilepsy can thereby be related to cognitive decline and poor neurological outcome. Seizures and spreading depolarization arise as characteristic activity from ischemic lesions but may also contribute to lesion progression and reorganization of the adjacent neural network and are therefore critical electrophysiological correlates of the pathophysiology. As an important structure for memory consolidation but also as a very sensitive area for epileptogenesis, the hippocampus is a crucial structure for investigating mechanisms underlying the pathophysiology of BBB-dysfunctional induced changes in synaptic plasiticity and neural network activity. To elucidate mechanisms underlying the pathophysiology I investigated with a multi-methodological approach different aspects of changes in rat hippocampus following neocortical photothrombosis using magnetic resonance imaging, intracranial pressure and electrophysiological measurements as well as gene expression analysis. Cortical photothrombosis was associated with early peri- ischemic BBB dysfunction that included the underlying, ipsilateral hippocampus and increased intracranial pressure, both preceding the occurrence of vasogenic edema. Intrahippocampal field potential recordings revealed electrographic seizures within the first week in two thirds of animals. Predominantly seizing animals displayed an increase in theta and reduction in gamma frequency bands indicating disturbed inhibitory activity. Synaptic interactions and plasticity were studied in parasagittal hippocampal slices at 24 hrs and 7 days post-stroke. Field potential recordings in CA1 and CA3 uncovered multiple population spikes, epileptiform episodes and spreading depolarizations at 24 hrs declining at day 7. However, input-output analysis revealed that fEPSP-spike coupling was significantly enhanced at 7 days. In addition, CA1 feedback and feedforward inhibition were diminished over the first week. Slices generating epileptiform activity at 7 days revealed impaired bidirectional long-term plasticity following high and low frequency stimulation protocols. Supporting these findings, microarray and PCR data confirmed changes in expression of astrocyte-related genes and suggested downregulation in expression of GABAA-receptor subunits. In conclusion, BBB dysfunction in the peri-infarct hippocampus is within the first week related to hyperexcitability, early disinhibition and abnormal synaptic plasticity. Thus, the data reveal a strong connection between hippocampal neural networks presenting epileptiform activity and disturbed oscillatory activity as well as long-term plasticity. These insights reveal possible new diagnostic monitoring opportunities in finding patients at risk for epileptogenesis and cognitive impairment associated with peri-lesional BBB-dysfunction.Erworbene Epilepsien in älteren Menschen resultieren häufig aus Hirnläsionen assoziiert mit Bluthirnschranken (BHS)-Störungen wie Schlaganfall, Trauma, Hirntumoren oder -entzündungen. Nach Schlaganfall entstandene Epilepsien können dabei mit kognitivem Abbau und schlechten neurologischen Ergebnissen verbunden sein. Krampfanfälle und Streudepolarisierungen (Spreading depolarizations) entstehen ferner oft als charakteristische Aktivität aus der ischämischen Läsion, können aber auch zur Läsionsausweitung und Reorganisation des anliegenden neuralen Netzwerkes beitragen und sind deshalb wegweisende elektrophysiologische Korrelate der Pathophysiologie. Als eine wichtige Struktur für die Gedächtniskonsolidierung aber auch als sensibles Areal der Epilepsieentstehung, ist der Hippokampus eine entscheidende Struktur um die pathophysiologischen Mechanismen zu untersuchen, die den BHSStörung induzierten Veränderungen der synaptischen Plastizität und der neuralen Netzwerkaktivitäten unterliegen. Zur mechanistischen Aufklärung der zugrundeliegenden Netzwerkpathophysiologie untersuchte ich verschiedene Aspekte der Veränderungen im Hippokampus der Ratte nach einer neokortikalen Photothrombose. Dabei verwendete ich vielseitige Methoden wie die Magnet Resonanz Tomographie, Hindruckmessungen, elektrophysiologische Ableitungen und Genexpressionsanalysen. Die kortikale Photothrombose war mit einer früh auftretenden peri-ischämischen BHS-Störung im darunterliegenden, ipsilateralen Hippocampus und erhöhtem Hirndruck assoziiert, welche der Entwicklung eines vasogenen Ödems vorrausgingen. Intrahippokampale Feldpotentialableitungen präsentierten innerhalb der ersten Woche nach Schlaganfall in zweidrittel der Tiere elektrographische Krampfanfälle. Vor allem krampfende Tiere zeigten sowohl einen Anstieg in Theta- als auch einen Abfall in Gammafrequenzbändern, was auf eine gestörte inhibitorische Aktivität hinweist. Synaptische Interaktionen und Plastizität wurden nach 24 h und 7 Tagen nach Schlaganfall in parasagittalen hippokampalen Hirnschnitten untersucht. Feldpotentialableitungen in CA1 und CA3 deckten multiple ‚population spikes’, epileptiforme Episoden und Streudepolarisierungen nach 24 h auf, welche nach 7 Tagen rückläufig waren. Allerdings zeigten Eingangs-Ausgangs-Analysen, dass die fEPSP-Spike Kopplung nach 7 Tagen signifikant erhöht war. Des Weiteren waren die feedback- und feedforward-Hemmungen in CA1 innerhalb der ersten Woche vermindert. Am 7. Tag präsentierten Hirnschnitte mit epileptiformer Aktivität eine beeinträchtigte bidirektionale Langzeitplastizität nach hoch- und niederfrequenten Stimulationsprotokollen. Unterstützend für diese Erkenntnisse bestätigten Microarray und PCR-Daten Expressionsveränderungen in Astrozyten-bezogenen Genen und deuteten eine verminderte Expression in GABAA- Rezeptor Subtypen an. Zusammenfassend lässt sich sagen, dass BHS-Störung im peri-Infarkt Hippokampus innerhalb der ersten Woche mit Übererregbarkeit, früher Disinhibition und abnormer synaptischer Plastizität assoziiert ist. Dadurch stellen die Daten eine enge Verbindung zwischen hippokampalen neuralen Netzwerken mit epileptiformer Aktivität und gestörter oszillatorischer Aktivität sowie Langzeitplastizität dar. Diese Erkenntnisse zeigen neue, etwaige diagnostische Überwachungsmöglichkeiten auf, um Patienten zu entdecken, die potentiell in Gefahr sind eine Epilepsie sowie kognitive Einschränkungen im Rahmen einer peri-läsionalen BHS-Störung zu entwickeln

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

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 (IM) and the persistent Na+-current (INaP). 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 IM combined with either a reduction in INaP or an increase in ILeak 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

Status epilepticus induces chronic silencing of burster and dominance of regular firing neurons during sharp wave-ripples in the mouse subiculum

Summary: Sharp wave-ripples (SWRs) are hippocampal oscillations associated with memory consolidation. The subiculum, as the hippocampal output structure, ensures that hippocampal memory representations are transferred correctly to the consolidating neocortical regions. Because patients with temporal lobe epilepsy often develop memory deficits, we hypothesized that epileptic networks may disrupt subicular SWRs. We therefore investigated the impact of experimentally induced status epilepticus (SE) on subicular SWRs and contributing pyramidal neurons using electrophysiological recordings in mouse hippocampal slices. Subicular SWRs expressed hyperexcitable features post-SE, including increased ripple and unit activity. While regular firing neurons normally remain silent during SWRs, selective disinhibition recruited more regular firing neurons for action potential generation during SWRs post-SE. By contrast, burster neurons generated fewer action potential bursts during SWRs post-SE. Furthermore, altered timing of postsynaptic and action potentials suggested distorted neuronal recruitment during SWRs. Distorted subicular SWRs may therefore impair information processing and memory consolidation in epilepsy