Synaptopathies: genetics, biophysics and circuit mechanisms of paroxysmal neurological disorders. (360G-Wellcome-104033_Z_14_Z)

Several neurological diseases characterised by paroxysmal symptoms, including epilepsy, migraine, ataxias and dyskinesias, exhibit strong heritability, yet the underlying genes and cellular mechanisms are largely unknown. In the rare cases where inheritance is Mendelian, the genes overwhelmingly encode proteins involved in synaptic transmission: ion channels, transporters and components of the neurotransmitter vesicle cycle. Polygenic variability in synaptic proteins is likely to account for the non-Mendelian heritability of common forms of these paroxysmal diseases. A possible explanation for their episodic nature is that homeostatic regulation of neuronal excitability and synapses partly compensates for alterations in the function of individual signalling molecules. Understanding the pathogenesis of these diseases requires a dialogue between clinical genetics and mechanistic studies of the synapse. We will apply deep phenotyping and sequencing to identify candidate genetic variant s in patients with paroxysmal neurological disorders, will harness biophysical insights into vesicle trafficking, ion channel function and synaptic integration to stratify these variants, and will study their consequences by systematic mutagenesis coupled with functional evaluation in vitro and in vivo. Conversely, we will use disease-associated mutations as insights into the mechanisms of synaptic transmission. The programme of research promises both to advance understanding of disease mechanis ms and identify therapeutic targets.