Molecular Neurophysiology: Ligand Gated Ion Channels in Neurological Diseases

Ligand gated ion channels mediate fast synaptic neurotransmission. Since this is one of the core features of the nervous system, there is hardly a neurological condition without involvement of synaptic neurotransmission. The development of the patch-clamp technique made it possible to investigate synaptic ion channel receptors functionally on the single molecule level as well as within defined neuronal networks. Combined with methods like cell culture, molecular cloning, functional expression, fluorescence microscopy, and ultrafast application techniques, the design of experiments suitable for the investigation of synaptic transmission in neurological disorders was made possible. Examples of our experimental work demonstrate the significance of molecular neurophysiology for the investigation of a broad spectrum of neurological disorders like immunological and neurodegenerative disorders or epilepsies. The direct functional interaction of specific antibodies with nicotinic receptors in myasthenia gravis and Guillain Barré syndrome could be studied by defined application of IgG fractions from patients to nicotinic receptors activated by pulse-wise transmitter application. The pivotal role of specific subtypes of glutamate receptor channels for neurodegeneration due to chronic excitotoxicity and Ca⁺⁺ overload of neurons can be demonstrated and in vitro testing of potential neuroprotective drugs becomes feasible. The pathophysiology of familial epilepsies caused by mutations of genes coding for inhibitory ligand gated GABAA receptor channels can be revealed by functional expression experiments that serve as a model of disease for pharmacological screening as well. Thus, molecular neurophysiology enables us to track functional impairment of the nervous system to the single molecule level and can serve in molecular diagnostics.