Misfiring or misfolding – role of Kv3 potassium channels in central hearing loss and neurodegeneration

• Applicant: Privatdozentin Dr. Conny Kopp-Scheinpflug
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Experimental and Theoretical Network Neuroscience ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 519114834

Hearing loss and neurodegeneration are health deficits that begin gradually and are usually multifactorial in origin. This makes it difficult to identify the causes, so that medicine currently concentrates on treating the symptoms rather than curing the causes. Despite decades of research in both fields, functional concepts that link hearing loss and neurodegeneration on a mechanistic level are lacking. This is partly because at the demographic level, direct and indirect factors are difficult to separate. At the cellular level, central hearing loss can be attributed to reduced temporal precision (timing) of action potentials in auditory neurons, while neurodegenerative diseases are usually associated with the formation of pathological intracellular protein aggregates. Taking this a step further, the timing of action potentials can be attributed to changes in the function of voltage-gated potassium channels and the formation of pathological protein aggregates is associated with increased intracellular calcium concentrations. Consequently, the primary aim of this project is to test the hypothesis that a common cellular mechanism underlies both diseases, hearing loss and neurodegeneration: intracellular calcium overload due to prolonged action potential duration as the cause of the toxic insult. Human spinocerebellar ataxia type13 is an autosomal dominant inherited disease that results in cerebellar atrophy, impaired motor coordination AND hearing loss in the form of impaired sound localization. All of this is caused by a single point mutation (R420H) in the KCNC3 gene, which codes for the Kv3.3 subunit of voltage-gated potassium channels. Using a new R420H mouse model created for this project, we will use neurophysiology to investigate how changes in action potential duration affect calcium influx into neurons. Prolonged action potentials should lead to reduced firing rates of the neurons and decreased temporal precision. This will be assessed at the neuronal circuit level by measuring pre- and postsynaptic activity. The expected increased intracellular calcium concentrations lead to overstimulation of downstream signaling cascades, which in turn increase transmitter release or cause protein misfolding and/or aggregation as precursors to neurodegeneration. We will use the findings of this project to identify common cellular mechanisms for hearing loss and neurodegeneration, to establish early auditory biomarkers for degeneration in other parts of the brain, and to initiate future research directions investigating how the natural age-related decline of Kv3 channels might underlie neurodegenerative disease mechanisms outside the R420H model. The aspect of investigating altered AP shapes as the beginning of a degenerative process rather than vice versa provides a conceptual turning point in our understanding of neuronal dysfunction and cell death.

• DFG Programme: Research Grants
• International Connection: United Kingdom
• Cooperation Partner: Professor Dr. Ian D. Forsythe