Doctoral Candidates:

• Markus Ballmann
• Nour Kassab El Dine
• Moxi Chen
• Zhaoying Li
• Jin Mengyao

MSc and BSc Students

Technical Assistance:

• Andreas Blaschke
• Dr. vet. Nina Bayer

Animal Management:

• Dr. Stefanie Monecke

In addition to institutional funds, financial support is provided by the German Research Foundation (DFG), the faculty’s internal commission for clinical research (KKF), and industry funds.

The laboratories are located on the campus of the Klinikum rechts der Isar. Various intra- and extracellular recording techniques and imaging systems are available. For recording from individual neurons, an infrared-guided patch-clamp rig is used, which has been additionally equipped with a UV laser. This allows neurotransmitter release to be triggered at visualized neurons via laser, enabling measurement of postsynaptic receptor activity in brain slice preparations. Additionally, the setup is equipped with a calcium imaging system. A particular highlight is the imaging setup for neuronal activity (VSDI), which represents the latest advancement in this type of measurement technology. This technique allows the observation of excitation spread over large brain slice areas using voltage-sensitive dyes incorporated into cell membranes. It is used to study, for example, thalamocortical activity relevant to anesthesia under the influence of various anesthetics. Furthermore, it allows the tracking of neuronal activity spread in the tri-synaptic circuit of the hippocampus, thereby investigating the effects of different pharmaceuticals at the network level. Additionally, by using afferent stimulation and extracellular recording techniques, synaptic sum activity in brain slice preparations can be analyzed.

The group primarily investigates the effects of centrally acting drugs on neurophysiological and neurodegenerative mechanisms. The focus of our research is on processes relevant to learning and memory, as well as β-amyloid-induced neurotoxicity in Alzheimer’s disease. In this disease, synaptic damage caused by β-amyloid is considered one of the main causes of the irreversible loss of neurons and a key pathophysiological correlate of the progressive dementia characteristic of the condition.

Specifically, intravenous, gaseous, and volatile anesthetics are studied for their effects on the function of voltage-gated ion channels, synaptic transmission, and synaptic plasticity in the hippocampus, neocortex, and amygdala of mice.

Focusing on dementia (particularly Alzheimer’s disease), the physiological effects of anesthetics, benzodiazepines, and centrally acting neurosteroids on the toxic effects of β-amyloid protein (Aβ) are characterized. We also examine the general effects of anesthesia on cognitive performance in vivo, both under normal and dementia-related conditions (Alzheimer’s disease).

Using histological, molecular biological, biochemical, imaging, and electrophysiological techniques, we aim to determine the extent to which anesthetics, benzodiazepines, and neurosteroids influence the synaptotoxic effects of β-amyloid.

We are also interested in the phagocytosis of dendritic spines controlled by astrocytes and microglia. These processes are crucial for synapse formation and elimination and play an important role in regulating synaptic activity. Proteins such as C1q, C3, Nectin, Megf10, and MERKT have significant physiological importance. Since cognitive performance is closely linked to the number and functionality of dendritic spines, we are investigating the influence of various anesthetics and β-amyloid on these mechanisms.

Additionally, adeno-associated viruses (AAVs) can be used in our experiments to transfer genes into specific neuronal populations (e.g., parvalbumin interneurons), allowing the precise enhancement or inhibition of neuronal activity in this specific neuron type. This enables the characterization of the role of these neurons in specific physiological processes (e.g., cellular processes responsible for learning and memory).

Anesthetics:

• Volatile Anesthetics:
  • Interaction of Isoflurane and Sevoflurane with synaptic transmission and synaptic plasticity in different brain regions
  • Influence of Isoflurane and Sevoflurane on learning and memory
  • Isoflurane, Sevoflurane, and POCD (Postoperative Cognitive Deficits): Possible long-term effects of anesthesia on cellular processes responsible for learning and memory.
  • Interneurons and anesthesia: Determining specific types of interneurons as GABAergic modulators and pharmacological targets in collaboration with Prof. Antkowiak (Tübingen)
• Xenon:
  • Interaction of Xenon with synaptic transmission and synaptic plasticity in different brain regions
  • How does Xenon affect thalamocortical circuits? Electrophysiological studies and imaging (VSDI)
  • Can positive effects of Xenon on learning and memory be demonstrated in vitro compared to Sevoflurane and Propofol? This includes studying long-term potentiation in hippocampal brain slices under both physiological and pathological conditions, such as with the addition of synaptotoxic β-amyloid.
  • How does Xenon, in comparison with volatile anesthetics, influence synapse elimination?

Perioperative Management:

The definition of perioperative anesthesia management has significantly evolved in recent years. Initially focused on a short perioperative window, it has now expanded to long-term monitoring to avoid the occurrence of postoperative delirium (POD) and postoperative cognitive deficits (POCD). Preoperative risk factors such as dementia, affective disorders, or stress-related conditions, which already negatively impact cognitive functions like learning and memory, can promote the development of POD and POCD.
The following questions are therefore relevant:

• Can preoperative EEG monitoring of sleep characteristics serve as a predictive biomarker for identifying risk groups (e.g., those with Alzheimer’s disease or disrupted neuroendocrine stress reactivity or depression) for the development of POD and POCD after anesthesia? Both short- and long-term effects of anesthesia on brain activity, emotionality, and cognitive functions are examined. (In collaboration with Prof. Chadi Touma (Osnabrück) and PD Dr. Thomas Fenzl (MRI, TUM).)

Neuroprotection:

• Modulation of GABA(A) receptor subunits by neurosteroids and anesthetics: Identification of molecular binding sites crucial for neuroprotection. (In collaboration with Prof. Antkowiak (Tübingen).)
• Clarification of the molecular, cellular, and systemic differences between benzodiazepines and neurosteroids. To what extent are different classes of interneurons involved in the alteration of network activity by benzodiazepines and neurosteroids? How are cellular mechanisms for learning and memory influenced? In the context of Alzheimer’s disease pathology, we aim to investigate the hypothesis that the use of neurosteroids, rather than benzodiazepines, is more advantageous in cases of pre-existing neurodegenerative damage and protects against further degeneration. (In collaboration with Prof. Antkowiak (Tübingen).)
• Studies on the significance of the perineuronal net (PNN) in physiological and pathological processes (e.g., long-term potentiation (LTP) and β-amyloid toxicity). (In collaboration with Prof. Peter Noakes (University of Queensland, Brisbane).)

Alzheimer's disease and Parkinson’s disease:

• The influence of low-dose glutamate receptor antagonists on β-amyloid toxicity: in vivo and in vitro experiments on learning and memory.
• Interaction of aggregation inhibitors with β-amyloid: in vitro and in vivo experiments in hippocampal brain slices. (In collaboration with Dr. H. Russ (Galimedix Therapeutics).)
• Interaction of IAPP (islet amyloid polypeptide) analogs with β-amyloid: in vitro experiments in hippocampal brain slices. (In collaboration with Prof. Dr. A. Kapurniotu (TUM).)
• Do neurosteroids improve neurocognitive abilities at different stages of disease in animals of a transgenic mouse model of Alzheimer’s disease? The significance of TSPO-dependent neurosteroid release on Abeta-induced synaptotoxic effects, focusing on processes relevant to learning and memory. (In collaboration with Prof. Dr. Jochen Herms (DZNE Munich).)
• Studies on the function of astrocytic TSPO protein in Alzheimer’s disease in relation to anesthesia. This project aims to analyze astrocytic calcium oscillations in vivo. The goal is to understand: (1) How astrocytic calcium oscillations are altered by neurodegenerative processes depending on anesthesia, and (2) whether this disrupted astrocytic function is dependent on TSPO receptor activation and can be influenced by neurosteroid-based therapeutic approaches. Understanding these mechanisms may help explain why anesthesia triggers the manifestation of neurodegenerative diseases and whether this can be prevented through preventive or perioperative neurosteroid-based therapy. (In collaboration with Prof. Dr. Jochen Herms (DZNE Munich).)
• Can the anesthetic gas Xenon, as a weak NMDA receptor antagonist, attenuate or eliminate the toxicity of various Aβ species in vitro and in vivo? This question will be investigated through studies on hippocampal long-term potentiation and neurodegenerative mechanisms in mice.

Anxiolysis:

• Pharmacological studies on the substance XBD173, an activator of the translocator protein (TSPO 18kD): Is XBD173 a potential alternative to benzodiazepines in perioperative management? Comparative studies of XBD173 and midazolam on anxiolysis, learning behavior, and memory in young and old mice.

Tumor Research:

• Studies on the compensation of radiation-induced inflammation through anti-inflammatory substances. The neurophysiological vitality and functionality in hippocampal brain slices of irradiated mice, as well as potential compensatory effects of fenofibrate and cannabidiol on brain function, are examined. (In collaboration with Prof. Dr. Gabriele Multhoff (MRI, TUM).)
• How do tumor cells influence neuronal activity to support tumor proliferation in pancreatic carcinoma? Using patch-clamp and calcium imaging techniques, we investigate electrical communication at a peripheral cancer cell-neuron synapse to characterize its function and explore potential therapeutic interventions. (In collaboration with Prof. Dr. Ekin Demir (MRI, TUM).)

Anxiolysis and Neuroprotection via TSPO Activation and Neurosteroid Release

• Rainer Rupprecht, Prof. Dr. med., Chief Physician, Bezirksklinikum Regensburg, Universitätsstraße 84, 93053 Regensburg
• Christian Wetzel, Prof. Dr. rer. nat., Department of Psychiatry and Psychotherapy, Regensburg, Universitätsstraße 84, 93053 Regensburg

Therapeutic Approaches to the Pathomechanism of β-Amyloid Protein

• Galimedix Therapeutics

Neurodegeneration

• Jochen Herms, Prof. Dr. med., German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Str. 17, 81377 Munich
• Prof. Dr. Stefan Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Str. 17, 81377 Munich
• Prof. Dr. Peter Noakes, School of Biomedical Sciences, University of Queensland, Australia

GABAA Receptors and Neuroprotection

• Bernd Antkowiak, Prof. Dr. rer. nat., University of Tübingen, Waldhörnlestraße 22, 72072 Tübingen

Islet Amyloid Polypeptide

• Aphrodite Kapurniotu, Prof. Dr. rer. nat., Technical University of Munich, Emil-Erlenmeyer-Forum 5, 85354 Freising-Weihenstephan

Tumor Research

• Gabriele Multhoff, Prof. Dr. rer. nat., Experimental Radiooncology and Radiation Biology, Klinikum rechts der Isar, Munich
• Ekin Demir, Prof. Dr. med., Department of Surgery, Klinikum rechts der Isar, Munich

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