Auswirkungen von Antiepileptika auf das fokale Freeze-Läsionsmodell: neue Erkenntnisse zur Pathophysiologie von Malformationen kortikaler Entwicklung

Malformations of cortical development (MCD) can lead to difficult-to-treat epilepsy in children and adults. They are characterized by physical abnormal tissue in the neocortex; however, it is often the area surrounding this malformation that is hyperexcitable. Antiepileptic drugs can be used to reduce the frequency or severity of seizures, but they do not target the relying cause of the epilepsy, only symptoms. I studied the effect of established and newer antiepileptic drugs in a model of MCD: the focal freeze lesion model (FFLM), that reproduces some of the characteristics of microgyria which is a frequent form of MCD. After noticing visually, a reduction in the volume of the hemisphere, I tested the hypothesis that the freeze lesion led to a wider reduction in brain size, using magnetic resonance imaging. I induced seizure-like events (SLE) using the potassium channel blocker 4 amino-pyridine. I located the onset site of SLE using electrophysiology combined with intrinsic optical imaging. This method also allowed to study the propagation of seizure-like event in the slice. The analysis of this data led to the identification of the onset site in the lesioned slices and in the two controls, contralateral side, and sham-lesioned animals. I also analysed the electrophysiological parameters of the SLE in the three groups. I performed experiments during which I bath applied one of five antiepileptic drugs (AEDs) of different generations with different targets, and I measured their impact on SLE duration, frequency, propagation, and onset-site. I showed and quantified for the first time a reduction of the volume of the lesioned hemisphere in the FFLM, limited to the neocortex. This could indicate a further involvement of the “healthy” normo-typic neocortex in the pathology. I confirmed that the perilesional area is the site of the initiation of spontaneous seizures. Taken together, these results can influence the treatments of MCD, notably surgical as removing the abnormal tissue would not be sufficient to prevent further seizures. In this work, I described the mode of actions of all five AEDs in this model, confirming or contradicting general knowledge on these molecules. I showed that the sodium channel blockers carbamazepine and lacosamide suppressed SLE in this model but not specifically in the lesioned slices. Zonisamide and acetazolamide which target respectively calcium channels and the carbonic anhydrase had more contrasted effects, reducing either the frequency or the propagation of SLE in the model. Both had no specific effect on the lesioned slices though. These results indicated that these four drugs can be efficient in MCD but that they do not target the abnormal networks. I also analysed the modes of action of the antiepileptic drugs and described whether they acted by limiting the initiation of SLE or by reducing the propagation of SLE. These data can be of great clinical use and influence the choice of AED (or the combination) prescribed in patients. Finally, I showed for the first time a specific effect of the sodium potassium chloride cotransporter 1 (NKCC1) blocker bumetanide in adult lesioned neocortex, when it had no effect in the controls. This result indicates the persistence of an immature cortical network in this model and is an important contribution to the current discussion on the use of NKCC1 blockers in the treatment of MCD. I discuss here the possible clinical implications of these results and their limitations.Malformationen der kortikalen Entwicklung (MCD) können bei Kindern sowie Erwachsenen zu schwer behandelbarer Epilepsie führen. Sie sind durch Gewebeanomalien im Neokortex erkennbar, wobei jedoch häufig das periläsionelle Gewebe übererregbar ist. Um die Häufigkeit oder Schwere von Anfällen zu verringen, werden Antiepileptika eingesetzt. Diese zielen aber nicht auf die eigentliche Ursache der Epilepsie ab, sondern nur auf das Symptom epileptischer Anfall. Ich habe die Wirkung von etablierten und neueren Antiepileptika in einem Modell der MCD untersucht, dem fokalen Freeze-Läsion Modell (FFLM). Dies bildet einige der Merkmale von Mikrogyrien, einer häufigen Form von MCD, nach. Im FFLM habe Ich untersucht und aufgezeigt, dass die Volumenreduktion in der läsioniellen Hemisphäre größer als der eigentliche Gewebeverlust ist, der bei der Nekrose durch die Kühlläsion auftritt. Dies könnte auf einen weiteren Einfluss des "gesunden" normotypischen Neokortex an der Pathologie hinweisen. Mit Hilfe elektrophysiologischer und intrinsischer optischer Signalaufzeichnungen bestätigte ich, dass die 4AP-induzierten Anfälle mehrheitlich im normotypischen periläsionellen Bereich begannen. Unterschiedliche Antiepileptika wurden in diesem Modell getestet, um 1. zu untersuchen, ob eine oder mehrere der Substanzen eine spezifische Wirkung auf das Modell haben, und um 2. ihre Wirkungsweise in diesem Modell zu untersuchen. Insbesondere bin ich der Frage nachgegangen, ob die untersuchten Antiepileptika (AEDs) die Entstehung von anfallsartigen Ereignissen (SLE, für seizure-like events) unterdrücken oder die Ausbreitung von SLE reduzieren. Ich wählte etablierte und neuere AEDs mit unterschiedlichen vermuteten Zielstrukturen und Wirkungsweisen aus, die Natriumkanalblocker Carbamazepin und Lacosamid, den T-Typ-Kalziumkanalblocker Zonisamid, den potenten Karbonanhydraseblocker Acetazolamid und schließlich den Chlorid-Cotransporter NKCC1-Blocker Bumetanid. Ich habe die Wirkungsweise aller fünf AEDs in diesem Modell beschrieben und damit das allgemeine Wissen über diese Moleküle bestätigt oder widerlegt. Carbamazepin und Lacosamid blockierten die SLE in allen Gruppen erfolgreich. Ihre Wirkung war nicht läsionsspezifisch. Zonisamid und Acetazolamid hatten intermediäre Wirkungen, indem sie die Häufigkeit oder Ausbreitung von SLE reduzierten, ohne sie vollständig zu blockieren, der Effekt war nicht läsionsspezifisch. Bumetanid blockierte die SLE in diesem Modell spezifisch, was das anormale Vorhandensein von NKCC1 in diesem kortikalen Netzwerk adulter Nager aufzeigte. Der NKCC1 ist normalerweise nur in unreifen neuronalen Netzwerken vorhanden und beeinflusst EGABA stark, indem er das GABA-Gleichgewicht in Richtung desdepolarisierenden GABA verschiebt. Diese Ergebnisse deuten auf das Fortbestehen eines unreifen Netzwerks in dem FFLM und damit auch bei MCD hin. Ich gehe in meiner Arbeit auf die möglichen klinischen Implikationen dieser Ergebnisse und ihre Limitationen ein

Reducing carbon emissions in aquaculture: Using Carbon Disclosures to identify unbalanced mitigation strategies

The production of Scottish Atlantic salmon (Salmo salar) involves a global supply chain with greenhouse gases (GHG) emitted at every step. With the UK government setting a net zero target by 2050, and the Scottish Government having committed to achieving net zero by 2045, the Scottish salmon aquaculture sector now needs to start to develop and implement comprehensive emissions reductions measures. The methods demonstrated here and the identified imbalances in carbon emissions mitigation strategies provide a route to support this process. We use two international aquaculture operators in Scotland, Grieg Seafood and Mowi, as case studies to understand the scale of GHG emissions in the industry, how these compare to mitigation strategies, and where reduction efforts should be focused. Environmental data disclosed to the Carbon Disclosure Project (CDP), which includes in-depth breakdowns of GHG emissions in Scope 1, Scope 2 and Scope 3 categories were used for the first time in this comparison. This was contrasted with interview data from academics, industry experts and NGOs to identify routes to the most effective mitigation and reduction strategy. CDP data successfully identify imbalances between GHG emissions and mitigation strategies, and demonstrate that while Scope 1 emissions in Scottish aquaculture operations are high compared to other countries, Scope 3 emissions represent the majority of emissions. In terms of mitigation, Scope 1 and Scope 2 strategies are adequate, but Scope 3 mitigation strategies do not match the scale of emissions, identifying a potential route for future carbon emission reductions

Macrolichen community structure in boreal forested wetlands on the island of Newfoundland, Canada

Forested wetlands provide important ecosystem services and vital habitat for numerous organisms. Epiphytic macrolichens are a common and abundant group of organisms in forested wetlands and, given their habitat specificity, they are of potential use as indicators of forested wetlands and spatial boundaries. However, little is known about the community structure of macrolichens in forested wetlands. To address this, I first tested for differences in macrolichen communities and habitat associations between wetlands and ecoregions. I found significant differences between forested wetland classes and ecoregions and identified potential indicator species. Second, I tested for differences in macrolichen communities among swamps, ecotones, and adjacent upland forests. I found that macrolichen community richness and diversity were highest in swamps and lowest in upland forests, and that macrolichen communities were significantly different among swamps, upland forests, and their ecotones. The results of this research highlight the potential use of macrolichens as indicators of forested wetlands and their spatial boundaries

Equitable representation of ecoregions is slowly improving despite strategic planning shortfalls

Representing all ecosystem types in protected areas (PAs) is central to international conservation agreements (i.e., Aichi Target 11) and ensuring the persistence of biodiversity. In response to these agreements, we have seen rapid growth of PA networks, but we do not know how this affects ecosystem representation. We explored this question by investigating drivers and trends of representation during periods of rapid land acquisition using the protection equality metric. We found that 90.9% of the studied countries have improved protection equality through time. Periods of rapid area expansion resulted in greater increases in protection equality, particularly through multiple, smaller PAs as opposed to fewer, larger PAs. However, observed increases may not be due to strategic planning, as protection equality from random PA allocation was statistically similar to observed values within six country-level simulations. Future international agreements should hold countries accountable to meeting multiple objectives and prioritize conservation outcomes over individual targets

Contrasting impacts of cultivated exotics on the functional diversity of domestic gardens in three regions with different aridity

Cultivated exotic plants are often introduced for their aesthetic value and today comprise a substantial fraction of the flora of urban domestic gardens. Yet, their relative contribution to the functional diversity of domestic gardens and how it changes across different climate zones is insufficiently understood. Here, we investigated whether the effects of cultivated exotics on functional diversity of three plant traits related to plant aesthetics (that is, plant showiness, plant height, and leaf area) varied in suburban domestic gardens in three regions (Minnesota, USA; Alt Empordà, Spain; and central South Africa) that differ in aridity. For each garden, we calculated the mean and variance of each plant trait considering all co-occurring species and also splitting them into co-occurring cultivated exotics and natives. Our results revealed that mean plant showiness increased linearly with the proportion of cultivated exotics both across and within studied regions. Moreover, co-occurring cultivated exotics were, on average, showier than natives in all regions, but differences in their trait variances were context-dependent. The interaction between cultivated exotics and aridity explained variation in mean plant height and leaf area better than either predictor alone, with the effect of cultivated exotics being stronger in more arid regions. Accordingly, co-occurring cultivated exotics were taller and had larger leaves than natives in warmer and drier regions, while the opposite was true in cooler and wetter regions. Our study highlights the need to consider the combined effects of exotic species and climate in future studies of urban ecology

To Achieve Big Wins for Terrestrial Conservation, Prioritize Protection of Ecoregions Closest to Meeting Targets

Most of the terrestrial world is experiencing high rates of land conversion despite growth of the global protected area (PA) network. There is a need to assess whether the current global protection targets are achievable across all major ecosystem types and to identify those that need urgent protection. Using recent rates of habitat conversion and protection and the latest terrestrial ecoregion map, we show that if the same approach to PA establishment that has been undertaken over the past three decades continues, 558 of 748 ecoregions (ca. 75%) will not meet an aspirational 30% area protection target by 2030. A simple yet strategic acquisition plan that considers realistic futures around habitat loss and PA expansion could more than double the number of ecoregions adequately protected by 2030 given current funding constraints. These results highlight the importance of including explicit ecoregional representation targets within any new post-2020 global PA target

A global database for metacommunity ecology, integrating species, traits, environment and space

The use of functional information in the form of species traits plays an important role in explaining biodiversity patterns and responses to environmental changes. Although relationships between species composition, their traits, and the environment have been extensively studied on a case-by-case basis, results are variable, and it remains unclear how generalizable these relationships are across ecosystems, taxa and spatial scales. To address this gap, we collated 80 datasets from trait-based studies into a global database for metaCommunity Ecology: Species, Traits, Environment and Space; “CESTES”. Each dataset includes four matrices: species community abundances or presences/absences across multiple sites, species trait information, environmental variables and spatial coordinates of the sampling sites. The CESTES database is a live database: it will be maintained and expanded in the future as new datasets become available. By its harmonized structure, and the diversity of ecosystem types, taxonomic groups, and spatial scales it covers, the CESTES database provides an important opportunity for synthetic trait-based research in community ecology