The role of ion channels, extracellular matrix and transmitter-receptors in saccadic disorders

• Applicant: Professorin Dr. Anja Horn-Bochtler
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Molecular and Cellular Neurology and Neuropathology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 434691666

The aim of this project is to investigate the role of ion channels, calcium-binding proteins and transmitter receptors in conjunction with extracellular matrix in pathophysiology of saccadic disorders. There are increasing indications that altered ion channel activity contributes significantly to the pathogenesis of various neurological disorders. These include neurodegenerative diseases that selectively affect particular subset of vulnerable neurons, including neurons of the saccade generators in the brainstem. Therefore, revealing the potential correlation will not only open the possibility for pharmacological intervention to saccadic disorders, but it will also test the hypotheses that states channelopathies as the etiology for multiple neurological disorders.The physiology of eye movements is the most intensively studied motor system, and the neuronal network for saccades (rapid eye movements between fixations) is particularly well-characterized. As numerous metabolic, autoimmune and neurodegenerative diseases are associated with saccadic disorders, the clinically well-accessible characteristics of saccades are increasingly used as biomarker for early detection of these neurological diseases. Moreover, combined with sensitive clinical measurements, mathematical modelling not only successfully identifies the source of symptoms in the saccadic circuitry, it also predicts electrophysiological properties that certain saccadic neurons must have, or lose in certain diseases.Anatomical and histochemical identification of saccadic neurons in monkey and human brainstem is one expertise of our research group. Recently, we have established an experimental approach that provides histological assessment of ion channel expression in conjunction with calcium-binding proteins and the specialized extracellular matrix. In this project we will first establish the ion channel profiles of saccadic neurons in monkey and will compare them to the histochemical signature in human control brainstem tissue. This will form the basis for examination of clinical cases with saccadic disorders (progressive supranuclear palsy, opsoclonus), where alterations in ion channel expression will be assessed to explain malfunction of certain saccadic neurons and of the saccadic circuitry. In this initial phase of the project we will focus on the investigation of saccadic burst and omnipause neurons, whose interaction is essential for saccade generation and whose malfunctions have been simulated in numerous models. In summary, with a method established in our lab, we will study the significance of ion channels as a cause for neurological disorders with saccadic deficits in human post-mortem tissue. We expect to study further neurological diseases with this approach, which will form the basis for pharmacological therapy.

• DFG Programme: Research Grants