March 23-24, 2020
8th Floor Seminar Room | CeMM |
Lazarettgasse | 1090 Vienna
Syngap1 (Synaptic Ras GTPase activating protein 1) is a protein that is critical for the development of cognition and proper synapse function. Mutations of the gene lead to neurodevelopmental disorder and are associated with intellectual disability. They are also proposed to play a significant role in other diseases such as epilepsy, autism, and schizophrenia.
For details on the program please visit the website. Please note that the symposium has been postponed to a later time.
ANA is proud to serve as co-organizer of this Symposium
Brain Awareness Week 2020
ANA 2019 Best Thesis Award: 2 winners
ANA congratulates Stefanie Geisler and Anna Tröscher,
completed her thesis work under the supervision of Gerald Obermair, Department of Physiology, Medical University Innsbruck, Austria. A link to the Medical University of Innsbruck thesis repository will be set here as soon as all her thesis work has been published.
Title: Redundant and specific functions of neuronal calcium channel α2δ isoforms in mutant mouse models and cultured neurons
Abstract: The four auxiliary α2δ isoforms of voltage-gated calcium channelshave been implicated in synaptogenesis and neurological disorders. Yet, the molecular mechanisms by which individual isoforms exert synaptic functions in health and disease remainlargely elusive. This lack of mechanistic insight can be partly ascribed to the fact that many brain regions simultaneously express α2δ-1, α2δ-2 and α2δ-3. Here we show that neuronal α2δ isoforms act partially redundant, but have also highly specific functions. By generating and characterizing three distinct double knockout mouse models, we first demonstrate a general importance in survival and development. The augmented severity of the phenotype in double compared to single knockout mice further supports the idea of functional redundancy. Nevertheless, volumetric analysis of brain sections revealed a reduced size of distinct brain regions, suggesting specific roles of individual α2δ isoforms. Indeed, using primary neuronal cultures from embryonic mice we show that presynaptic overexpressionof the α2δ-2 isoform strongly increases clustering of postsynaptic GABAA-receptors (GABAAR) in GABAergic synapses. Strikingly, presynaptic α2δ-2 exerts the same effect in glutamatergic synapses, leading to an abnormal localization of GABAARs opposite glutamatergic nerve terminals. Employing super-resolution microscopy we further demonstrate that this mismatched synapse formation is caused by an aberrant wiring of glutamatergic presynaptic boutons with GABAergic postsynaptic positions. The property of α2δ-2 to induce mismatched synapses is independent of the prototypical cell-adhesion molecules α-neurexins. However, exclusion of a single alternatively spliced exon is essential for the trans-synaptic recruitment of GABAAR. Taken together, the findings presented in this thesis propose that α2δ isoforms regulate synaptic connectivity of glutamatergic and GABAergic neurons depending on exon usage. Our results thus provide a novel mechanistic explanation for how abnormal α2δ subunit expression can result in aberrant neuronal wiring associated with neurological disorders, including epilepsy and autism.
completed her thesis work under the supervision of Jan Bauer, Division of Neuroimmunology, CBR, Medical University of Vienna. Here you find her complete thesis.
Title: Inflammation and Viruses in Epilepsy
Abstract: Epilepsy is one of the most common neurological diseases but a third of patients do not respond to pharmacological treatment. Of those, many suffer from immune-mediated epilepsy, which can arise from the innate and adaptive immune system. Adaptive immune reactions can comprise of a T cell-or a humoral response. Depending on the immunological pathway activated and the brain area affected, the symptoms vary. Antibody-mediated encephalitis, such as anti-leucine-rich glioma-inactivated (LGI)-1 encephalitis, leads to limbic encephalitis, accompanied by memory disturbances, psychosis and seizures. T cell-mediated encephalitis, for example Rasmussen encephalitis (RE), causes seizures and severe brain atrophy, and hence cognitive defects. Many questions regarding immune-mediated epilepsies have not been answered yet and are difficult to address due to lack of tissue or its scarcity. Hence, we took advantage of a natural animal model, in which cats develop antibodies againstLGI1 and show symptoms similar to the human disease to analyze changes outside the hippocampus in LGI1-encephalitis. We could show that T cell infiltrates occur brain-wide and do not overlap with blood-brain-barrier leakage. Further a tight-junction protein is lost in the hippocampus and the amygdala, causing immunoglobulin leakage, leading to complement deposition on neurons and hence neurodegeneration. In addition, we established a method to perform whole-genome transcriptomic studies on minimal amounts of formalin-fixed paraffin-embedded tissue to identify innate and adaptive immune responses in RE, a prime model of T cell-mediated diseases. We were able to show that small microglia nodules precede the T cell influx, providing an inflammatory microenvironment characterized by endosomal Toll-like receptor (TLR) and inflammasome upregulation. With disease progression, T cells intermingle with the microglia nodules, where they attack and kill neurons. Neonatal microglia cultures showed similar expression profiles upon TLR3 stimulation to what was observed in RE, indicating a TLR induced inflammatory reaction. Taken together, we were able to explain human pathology underlying pathomechanisms leading to two different forms of drug-resistant epilepsy.