1. Neuroimmunology-Munich
  2. Our Labs
  3. Liebscher Lab

Liebscher Lab – Circuits in CNS disorders

  • Our Aim

    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.

    Our Approach

    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.

    Some of our current projects

    Circuit mechanism of upper motor neuron degeneration in ALS

    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.

    The role of astrocytes in ALS circuit dysfunction

    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.

    Anti-NMDAR autoimmune encephalitis

    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.

    Contact

    Dr. med. Sabine Liebscher, PhD
    Sabine.Liebscher@med.uni-muenchen.de