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

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
 
Final Report Year 2024

Final Report Abstract

Eye movements are essential for visual image stabilization during head and body motion, but also for visual orientation by saccades, which direct the fovea of the retina to targets of interest. Saccades are very fast but must be accurate, which is achieved through the precise and well-timed firing of mainly two highly active neuronal groups in the brainstem: burst neurons and omnipause neurons, which are controlled by cerebellar pathways through the fastigial nucleus. Malfunction of these neurons may result in slowed or oscillatory eye movements as found in opsoclonus. The absence of structural lesions of burst and omnipause neurons in these diseases and the development of neuromimetic models led to the hypothesis that the membrane biology of these neurons or the cerebellum might be disturbed. In the funded project we used immunohistochemical methods to investigate the expression of ion channels, calcium-binding proteins, perineuronal nets, which all enable high firing rates of neurons, in brainstem sections from rhesus monkeys and human controls. The findings were then compared to corresponding stainings on brain stem sections from a case with opsoclonus. We showed that burst and omnipause neurons in monkey and human contain the endowment of ion channels that enable high discharge rates for bursts (more than 1000 Hz) or sustained tonic activity (as in the omnipause neurons). No qualitative differences were found for the ion channel profile in omnipause and burst neurons in the opsoclonus case. However, in the cerebellum of the opsoclonus case there was a slight reduction of Purkinje cells and in their target neurons in the fastigial nucleus a significant expression of the GABA synthesis enzyme glutamate decarboxylase was observed. In a study of two motoneuron types of the extraocular muscles, we further showed that the recently discovered differences in firing rate and threshold in these motoneurons are reflected in different ion channel profiles. Overall, this research solidified the immunohistochemical method as a valid tool for indirectly assessing the physiological properties of various neurons in the oculomotor system in monkey and human, which can be applied to clinical post-mortem cases. The data obtained can be fed back into models to obtain predictions for the expected eye movement disorders, but also to develop drug options for therapies.

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