Emmy Noether Junior Research Group - Cellular and Circuit Mechanisms of Upper Motoneuron Degeneration in Amyotrophic Lateral Sclerosis (ALS)
- Project Leader: Dr. Sabine Liebscher
- Affiliation: Institute of Clinical Neuroimmunology
- Funding: since 2017
The degeneration of upper motoneurons (OMN) is a major feature of amyotrophic lateral sclerosis (ALS), a devastating disease characterized by the joint death of OMN in the cortex and lower motoneurons in the spinal cord. Nevertheless, little is known about the dysfunction of upper motoneurons. New findings now suggest that OMN are affected very early in the disease, even before lower motoneurons show signs of degeneration. A major feature is changes in intrinsic excitability. These are described in early stages as hyperexcitability, based on a dysbalance between excitation and inhibition, which may affect cells other than those primarily affected in the disease. I will therefore analyze important functional units within the motor cortex using mouse models of ALS to uncover new aspects of the cortical pathology of ALS that ultimately lead to OMN degeneration. These are not only structural and functional changes of OMN, but also upstream neurons in layer II/III, which innervate OMN, intratelencephalic neurons, such as corticostriatal neurons, which provide intralaminar input on OMNs, as well as different types of interneurons, which are intricately reciprocally linked to each other to regulate activity within an area. In addition, non-cell-autonomous processes mediated by microglia and astrocytes are involved in the pathogenesis of ALS. Since both cell types are strongly involved in the regulation of synapses and thus of circuits, dysfunctions of these cell types result in a significant impairment of neuronal integrity. Using two-photon microscopy, the structural and functional changes of defined cell populations are observed and correlated during the course of the disease in awake animals. With this approach I am able to detect early changes of neuronal dysfunction, such as synaptic instability, and to determine their consequences for the respective nerve cell by following its response characteristics. Furthermore, I will determine whether these structural and functional dysfunctions are due to molecular changes such as the increase of intracell. calcium, the aggregation of proteins or the induction of apoptosis mechanisms. I plan to use these studies to detect a sequence of specific processes within the circuit of the motor cortex that ultimately leads to the destruction of OMN. These findings should contribute to the identification of new therapeutic approaches.
Source: GEPRIS (Text), University Hospital (Picture)