Liebscher Lab – Circuits in CNS disorders

Alterations in neuronal structure, function and connectivity are key features of several CNS disorders and do not only represent the basis for the cognitive or behavioral symptoms typical of a given disorders, but moreover can significantly trigger and fuel degenerative processes. The overall aim of our work is thus to identify and modify key regulatory elements of neuronal circuits in a disease-stage and region-specific manner. We mainly focus on the neurodegenerative disease Amyotrophic lateral sclerosis that is characterized by the degeneration of motor neurons in the cortex and spinal cord. Circuit mechanisms also play a role in neuroimmunological diseases, in which antibodies and immune cells attack neuronal structures. Patients frequently suffer from permanent neuronal damage even after the cessation of the initial immune attack. We thus strive to gain insight into how neuronal circuits are affected in autoimmune processes targeting CNS structures, such as in Anti-NMDA receptor autoimmune encephalitis.

To unravel structural and functional deficits of subtypes of neurons or glia cells, our work largely relies on in vivo two-photon imaging in behaving mice using transgenic mouse lines (and passive infusion models) in combination with genetically encoded indicators. Our work is complemented by neuronal tracing techniques, correlative immunohistochemistry, transcriptomic and proteomic analyses and putative targets are validated in human samples. Treatment strategies comprise amongst others chemogenetic manipulation of dedicated cellular populations.

Amyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease, characterized by the death of upper and lower motor neurons in cortex and spinal cord, respectively. Cortical hyperexcitability is an early feature observed in ALS patients and believed to also contribute to the degeneration of lower motor neurons. In this project we thus seek to understand the cellular and circuit mechanisms underlying cortical hyperexcitability in the disease. To address this question we use in vivo two-photon calcium imaging in behaving mice to investigate neuronal activity levels and response properties of different elements of the motor cortex microcircuitry across different stages of the disease in transgenic mouse models.

Astrocytes, the most abundant non-neuronal cells in the brain, have been suggested to play a causal role in ALS pathophysiology, but actual mechanisms remain poorly understood. Both a toxic gain as well as a loss of physiological function could potentially be involved. To investigate astrocyte function in vivo, we combine in vivo calcium imaging to characterize the complexity and alterations of astrocytic signals in health and disease. These experiment are complemented by transcriptomic and proteomic analyses to pinpoint molecular candidates that contribute to astrocyte dysfunction. Genetic rescue experiments shall then be exploited to restore astrocyte function and probe its impact on motor neuron health and survival.

Autoimmune antibodies targeting subunits of the NMDA receptor cause a severe disease named anti-NDMAR encephalitis. Patients suffering from the disease display a typical sequence of symptoms, ranging from initial flu-like prodromes, followed by psychiatric symptoms mimicking e.g. psychosis and later neurological symptoms, including epileptic seizures, movement disorders, aphasia or dysautonomia. If treatment is commenced early enough patients can recover, however, many will still suffer from long-term deficits in cognition or affect. We strive to gain insight into how neurons and neuronal networks are affected by the autoantibodies to cause this large set of symptoms and which deficits remain even to cause more permanent deficits in cognition. To address these questions we use a mouse model of the disease based on the passive transfer of autoantibodies. We monitor neuronal activity and response properties in one of the brain areas, which is mainly affected by the autoantibodies – the hippocampus. To characterize response properties, mice are maneuvering a track in a virtual reality environment, while the activity of up to hundreds of neurons is recorded by means of calcium imaging throughout the course of the disease.

Jelena Scekic-Zahirovic*, Inmaculada Sanjuan-Ruiz*, Vanessa Kan, Salim Megat, Pierre De Rossi, Stéphane Dieterlé, Raphaelle Cassel, Marguerite Jamet, Pascal Kessler, Diana Wiesner, Laura Tzeplaeff, Valérie Demais, Sonu Sahadevan, Katharina M. Hembach, Hans-Peter Muller, Gina Picchiarelli, Nibha Mishra, Stefano Antonucci, Sylvie Dirrig-Grosch, Jan Kassubek, Volker Rasche, Albert Ludolph, Anne-Laurence Boutillier, Francesco Roselli, Magdalini Polymenidou, Clotilde Lagier-Tourenne, Sabine Liebscher# and Luc Dupuis#, Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects, Nature Communications, 2021, 12:3028

Jelena Scekic-Zahirovic IS-R, Vanessa Kan, Salim Megat, Pierre De Rossi, Stéphane Dieterlé, Raphaelle Cassel, Pascal Kessler, Diana Wiesner, Laura Tzeplaeff, Valérie Demais, Hans-Peter Muller, Gina Picchiarelli, Nibha Mishra, Sylvie Dirrig- Grosch, Jan Kassubek, Volker Rasche, Albert Ludolph, Anne-Laurence Boutillier, Magdalini Polymenidou, Clotilde Lagier-Tourenne, Sabine Liebscher*, Luc Dupuis: Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses. BioRxiv 2020. (* co-senior author)

Steffen Jones, Postdoctoral student

I joined the lab as a post-doctoral researcher in 2022, working on mechanisms of cortical circuit dysfunction in ALS via in vivo calcium imaging and electrocorticogram recordings. I previously studied MSci Pharmacology at UCL and completed my PhD with Dr Gabriele Lignani, studying the role of homeostatic plasticity in epileptogenesis at UCL’s Institute of Neurology using single-cell electrophysiology and in vivo depth electrode recordings. My key academic interests are the roles of GABAergic interneurons in neurological disease and understanding how neural circuits undergo maladaptive plasticity in response to pathophysiological activity, both of which are key emerging themes in neurodegeneration research. At home, I enjoy playing guitar, reading, running, and playing badminton.

Christopher Douthwaite, PhD student

I grew up in the north of England and studied Neuroscience at the University of Leeds, UK, which included a year researching synaptic dysfunction in Alzheimer’s Disease at Janssen Pharmaceuticals, Belgium. I am a PhD student in the Graduate School of Systemic Neurosciences Munich, interested in neural circuit alterations that occur with psychiatric disorders. My project focusses on how the hippocampus guides the activity of the prefrontal cortex during spatial working memory. Outside of the lab, I enjoy playing football, taking advantage of Munich’s river surfing spots and exploring the alps skiing and hiking.

Shenyi Jiang, PhD student

I joined the Liebscher lab in the spring of 2020 as a PhD student. My current project aims to understand how chronic endoplasmic reticulum stress and stress granule formation based on aberrant phase transition influence the structural plasticity of synapses in vivo. I completed my bachelor’s degree in Biological Sciences at Sichuan University, China, where I primarily explored the complexity and beauty of neural networks on fruit flies in Dr. Haihuai He’s lab. After graduation, I did an internship in Prof. Qing Richard Lu’s lab, probing oligodendrocyte development in mice. I received her master’s degree in Neuroscience at University College London, UK. My master’s project addressed amyloid pathology and microglia activity in Alzheimer’s Disease under Prof. Frances Edwards’ supervision. In my spare time, I enjoy travelling, hiking, listening to symphony orchestras and rock music.

Vanessa Kan, PhD student

I am originally from Hong Kong and have lived in Canada and the U.S. before moving to Germany to study the cortical pathology in ALS. During my academic and research career in Hong Kong, I have always adopted ex vivo and in vitro techniques involving brain tissues, immunohistochemistry and cell culture to answer questions pertaining to neuroscience and cell biology topics. My previous experience thus prompted me to explore a new territory comprising in vivo two-photon imaging in awake behaving animals. Science is not the only thing I am passionate about, I also love travelling, being outdoors (the mountains) and in the kitchen. An occasional run in the afternoon in the woods close to the lab definitely boosts my dopamine levels! When I am stressed, I bake  which is not so bad for the people around me.

Liliana Ziegler, MD student

I was born in Bogotá, Colombia, to a German father and a Colombian mother. After spending my early childhood years in Colombia, I permanently moved to Germany when I was six years old. I attended high school in the city of Nuremberg and moved to Munich after graduation to study medicine at LMU Munich. I joined the Liebscher Lab in the spring of 2022 to investigate circuit mechanisms of cortical hyperexcitability in a mouse model of ALS, employing techniques such in vivo two-photon imaging, immunohistochemistry as well as behavioural experiments. In my spare-time, I enjoy swimming to clear my head. I also enjoy reading a lot and have been writing short stories myself.

XiaoQian Ye, PhD student

I grew up and studied Physics at Fudan University, China, and had experience in consulting industry, covering advanced technology manufacturing market and policy. With growing interest in cognitive neuroscience and neurodegenerative diseases, I completed my master’s degree in Computational Neuroscience and Cognitive robotics at the University of Birmingham, UK, where I was working on brain network dynamics across sleep stages using fMRI imaging technology and network analysis approaches (Dr Andrew Bagshaw Lab), and a second project on deploying virtual reality technologies (Oculus and Phantom), exploring human visuomotor transformation under Dr Sang-Hoon Yeo. Further diving into neurodegenerative diseases I joined in Liebscher Lab at the end of 2017 as a PhD student. I am working on astroglial dysfunction, a potential circuit contributor to upper motor neurodegeneration in ALS, using the state-of-the-art in-vivo imaging and integrating a broad range of molecular biology and immunological technologies together with computational analyses. Outside of the lab, I enjoy nature, life in Munich and exploring European art and history.

Zeynep Günes, PhD student

I am originally from Turkey. I completed my Bachelor`s degree in Biology at the Middle East Technical University in Ankara before I was admitted to the Fast-Track PhD program at the GSN-LMU. My project focuses on exploring circuit mechanisms that are potentially contributing to lower motor neuron degeneration in ALS. By doing so, I also focus on neuronal and glial cell function in the disease. In my free time, I enjoy doing “improv”, traveling, volunteering and organizing/participating in science communication events.

Riddhi Petkar, Master student

I was born and raised in India. I joined the Liebscher lab in June 2022 for my master's thesis project. I am 5th year BS-MS student at Indian Institute of Science Education and Research(IISER), Pune. My project focuses on understanding the role of microglia in TDP-43 pathology in ALS. I employ in vivo imaging, immunofluorescence plus confocal imaging to answer this question. Previously, I have worked with Dr. Raghav Rajan at IISER Pune. My project aimed at mapping of behavioural phenotypes following intercollicular complex stimulation in zebrafinches. During my bachelor's and master's, I have worked on several other projects, where I used electrophysiology, behavioural experiments, imaging and bioinformatics to answer various neuroscience questions. In my spare time, I enjoy travelling, reading novels, watching dramas and cooking.

Olivia Oh Wan Cheng, Master student

I was born in Malaysia and have partially spent my childhood in Taiwan. I obtained my Bachelor’s degree in Japan at the University of Tsukuba.
I have always been fascinated by biomedical sciences and human pathophysiology because I think doing research in this field is something meaningful in terms of helping people to not lose their love ones. I am currently doing my Master thesis investigating a possible genetic treatment for ALS in the Liebscher lab. Outside of the lab, I enjoy traveling, diving, snorkelling and swimming.

My main goal is to understand the basis – or in other words the neural correlates – of altered cognition and behavior typical of neurodegenerative diseases, such as Alzheimer‘s disease or Amyotrophic lateral sclerosis/Frontotemporal dementia, in order to identify novel circuit-based therapeutic targets to prevent disease progression and restore these deficits.

Training

2000 – 2007 Medical school, Technical University Dresden

2007 MD and medical license, University Hospital Dresden

2007 – 2008 Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, NY, Research Associate

2008 – 2014 MPI of Neurobiology, Dept. Synapses – Circuits – Plasticity & LMU, Adolf-Butenandt-Institute, Dept. of Metabolic Biochemistry, PhD

Academic positions & appointments

2014 – 2017 LMU, Clinician Scientist Group, Institute of Clinical Neuroimmunology, Group leader & University Hospital Munich, Dept. of Neurology, Resident

since 2017 Emmy Noether group leader

Awards & honors

2001 – 2008 Scholarship German National Academic Foundation

2008 Lohrmann Medal, Technical University Dresden

2008 – 2014 Member International Max Planck Research School

2008 – 2014 Member Graduate School of Systemic Neurosciences

2014 Independent group leader award - Clinician Scientist Program by the Munich Cluster for Systems Neurology

2017 Emmy Noether research grant

2017 Member of the Young Center of the Center for Advanced Studies, LMU Munich

2018 Member AcademiaNet, Robert Bosch

2019 Principal Investigator, Marie Curie Actions, Innovative Training Network ‘SAND’

5 key papers

Zambusi A, Novoselc KT, Hutten S, Kalpazidou S, Koupourtidou C, Schieweck R, Aschenbroich S, Silva L, Yazgili AS, van Bebber F, Schmid B, Möller G, Tritscher C, Stigloher C, Delbridge C, Sirko S, Günes ZI, Liebscher S, Schlegel J, Aliee H, Theis F, Meiners S, Kiebler M, Dormann D, Ninkovic J. TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury. Nat Neurosci. 2022 ;25(12):1608-1625.

Korzhova V., Marinković P., Njavro, J.R., Goltstein P.M., Sun F., Tahirovic S., Herms J., Liebscher S.: Long-term dynamics of aberrant neuronal activity in Alzheimer’s disease transgenic mice. Communications Biology 2021 ;4(1):1368.

Steffens H., Mott A. C., Li S., Wegner W., Svehla P., Kan W.Y.V., Wolf F., Liebscher S.# and Willig K.#: Stable but not rigid: Chronic in vivo STED nanoscopy reveals extensive remodeling of spines, indicating multiple drivers of plasticity. Sci Adv. 2021;7(24):eabf2806. # equal contribution

Scekic-Zahirovic J., Sanjuan-Ruiz I., Kan V, Megat S., De Rossi P., Dieterlé S., Cassel R., Kessler P., Wiesner D., Tzeplaeff L., Demais V., Muller H.P., Picchiarelli G., Mishra N., Grosch S., Kassubek J., Rasche V., Ludolph A., Boutillier A.-L., Roselli F., Polymenidou M., Lagier-Tourenne C., Liebscher S.# and Dupuis L.#: Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects. Nat Commun. 2021, 12(1):3028. # equal contribution

Liebscher S, Keller GB, Goltstein PM, Bonhoeffer T, Hübener M: Selective Persistence of Sensorimotor Mismatch Signals in Visual Cortex of Behaving Alzheimer’s Disease Mice. Current Biology 2016, 26:956–964.

Liebscher Lab – Circuits in CNS disorders

Our Aim

Our Approach

Some of our current projects

Circuit mechanism of upper motor neuron degeneration in ALS

The role of astrocytes in ALS circuit dysfunction

Anti-NMDAR autoimmune encephalitis

Contact

Dr. med. Sabine Liebscher, PhD

We gratefully acknowledge support for our work by the following agencies:

Emmy-Noether-Grant by the German Research Foundation (DFG)

Marie Sklodowska-Curie Actions: Innovative training Networks SAND

Munich Cluster for Systems Neurology (SyNergy)

Deutsche Gesellschaft für Muskelkranke e.V.

Friedrich Bauer Stiftung

LMU excellent

FöFoLe LMU

Graduate School of Systemic Neurosciences

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