Madry group

Our main research focus is on the physiology of microglia, the brain’s innate immune cells.

For many years microglia gained attention mainly because of their immunological role. However, this view has fundamentally changed due to enormous methodological advances and gain in knowledge, in particular in the last decade. It is now becoming increasingly clear what essential role these glial cells, located at the interface between the nervous and immune systems, play in brain development and homeostasis, both under physiological and especially pathological conditions. Microglia are by no means just passive bystanders, which only become active in the event of brain injury or by invading pathogenic agents, but they permanently survey the brain parenchyma very effectively with their highly dynamic cellular processes - a unique property of these cells. By dynamically interacting with neurons and other CNS cells, microglia keep a constant eye on the function of neurons and react immediately to any disturbances or injuries. Their primary goal is to protect the brain from damage and to maintain homeostasis. Due to their ability to sense changes in neuronal activity, microglia can target specific neuronal structures and influence synaptic transmission, excitability and plasticity of neurons. In turn, these processes can lead to changes in the function of neuronal networks and affect behavior.

Apart from their physiological role, microglia are also involved in almost all neurological diseases, including traumatic, ischemic, infectious, psychiatric and neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease, which affect millions of people worldwide. However, depending on the severity and duration of the pathological condition, microglia may lose their initial protective properties and adopt a potentially damaging activation state that exacerbates disease progression. Due to their disease-modulating role, microglia are nowadays considered important targets for therapeutic intervention, as evidenced by the current increasing number of microglial-related clinical trials.

Specifically, our research focus is on the functional role of microglial receptors and ion channels and their associated signaling pathways. Our overall goal is to understand how these receptor-driven mechanisms regulate microglial function under physiological and pathological conditions and thereby influence basic neuronal function and disease processes.

Our approach is based on three central pillars addressing the following questions:

(1) Investigation of physiological interactions between microglia and neurons

• What mechanisms regulate the high dynamics of microglia as a major prerequisite for their interaction with neurons?
• What are the consequences of loss of function or total absence of microglia on neuronal development and neuronal function?
• To what extent do microglia influence excitatory and inhibitory neurons and what are the implications for neuronal network function?

(2) Exploring functional changes of microglia under pathological conditions in the context of neurodegeneration

• What is the role of ion channel-mediated mechanisms in the generation and release of pro-inflammatory immune modulators in activated microglia?
• To what extent do the electrical membrane properties of microglia (as an important cellular function) differ under neurodegenerative conditions in an animal model of AD compared to the healthy state?
• What are the consequences for the disease processes associated with Alzheimer's disease?

(3) Translation of findings generated in animal models into the human context using acutely resected human brain tissue

• What are the morphological and functional differences of microglia in human brain tissue compared to mice?
• What is the therapeutic potential of the mechanisms identified in mouse models that regulate microglial activation and their inflammatory processes?

Our previous work has identified, among other things, a key microglial signaling pathway that regulates the dynamics and morphology of microglia in the healthy brain, and controls the release of proinflammatory substances under pathological conditions (see Madry et al., Neuron 2018; Madry et al., PNAS 2018). Building on these findings, a current thematic focus of our research is study these mechanisms for their contribution in neurodegenerative diseases and modulation of neuronal function (see review in Izquierdo et al., TINS 2019).

To achieve these goals, we apply a wide range of state-of-the-art techniques and analytical methods, focusing on electrophysiological (whole-cell patch clamp recordings, extracellular field potential recordings), imaging (multi-photon and confocal microscopy) and molecular biological methods (cell culture, viral expression, immunohistochemistry). Experimentally, we work primarily on brain slice preparations from rodents as well as acutely resected human brain tissue, using pharmacological and genetic tools that are essential for the study of cellular processes. In addition, we interdisciplinary collaborate with other basic scientific and clinical research groups within Charité, including the institutes of neuropathology, psychiatry and biochemistry.

We receive funding from the DFG, foundations (Alzheimer Research Initiative Germany) and industrial pharmaceutical partners.

Inquiries about joining our team and on current projects are welcome and can be sent to christian.madry(at)charite.de.