Cellular and Circuit Mechanisms of Upper Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis (ALS)

• Applicant: Professorin Dr. Sabine Liebscher
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2017 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 326014787

The degeneration of upper motor neurons (UMN) represents a cardinal feature of Amyotrophic Lateral Sclerosis (ALS), a devastating disease that is characterized by the joint impairment of upper and lower motor neurons (LMN) in cortex and spinal cord, respectively. However, research in the past has strongly focused on the study of lower motor neuron impairment, while little is known about the mechanisms governing UMN dysfunction. Recent findings suggest that UMNs are affected very early in the disease and that their dysfunction precedes the degeneration of LMN. One key characteristic, not only prominent in ALS, but also in other neurodegenerative diseases, are changes in intrinsic excitability. These are reported in prodromal stages of the disease as hyperexcitability, caused by a dysbalance between excitation and inhibition, which notably can affect cell types other than the actual prime target of the respective neurodegenerative disease in a hitherto unknown sequence. Understanding how different components of neural circuits are compromised in the course of the disease is, thus important in order to identify new therapeutic targets. This proposal is aimed at investigating key functional units within the motor cortex microcircuit in ALS mouse models to unravel new aspects of the cortical pathology in the disease that ultimately lead to UMN degeneration. These encompass structural and functional alterations of not only UMN, but also upstream cells in cortical layer II/III driving UMN, as well as intratelencephalic neurons, such as corticostriatal neurons, providing intralaminar input and multiple classes of interconnected interneurons regulating activity within an area. Moreover, non-cell autonomous processes, conveyed by microglia and astrocytes, were suggested to play an important role in ALS pathogenesis. As both are strongly involved in the regulation of circuits, their dysfunction likely has a major impact on neuronal health. I will employ state-of-the-art in vivo two-photon imaging in awake mice combined with molecular approaches to selectively record from defined cell populations, such as inhibitory subtypes, UMNs or layer II/III cells, to monitor and correlate structural and functional alterations of neurons and glia cells throughout the course of the disease. This approach should enable me to capture early changes of neuronal dysfunction, such as synapse instability, and to address its impact on the neuron s fate, by characterizing their consequences on neuronal response properties. Moreover, I will assess whether structural and functional alterations hinge on molecular changes, such as increased intracell. calcium, the formation of intracell. aggregates or signs of apoptosis. I believe that with these studies I can elucidate a sequence of events occurring within M1 circuits that governs the degeneration of UMN and which hopefully helps identifying new therapeutic strategies.

• DFG Programme: Independent Junior Research Groups