| Project Detail |
The episodic ataxias are a group of hereditary conditions with recurring paroxysms of cerebellar dysfunction. They are rare; however they share important similarities to other more prevalent paroxysmal disorders such as migraine and epilepsy. The prototypic cerebellar cortex paroxysmal disorder is Episodic ataxia 1 (EA1), which is linked to dominantly inherited missense mutations in the Kv1.1 potassium channel subunit. Work from an animal model harbouring a human EA1 mutation reveals altered synaptic function at basket cell terminals in the cerebellar cortex. However how EA1 mutations affect basket cell regulation of Purkinje cell firing is unclear, possibly due to unforeseen changes in a specialized inhibitory structure called the pinceau. Furthermore the mechanism whereby local synaptic deficits extend to global cerebellar cortex network dysfunction during attacks of incoordination is unknown. This MSC research action aims to understand these processes using a combination of cutting edge in vitro and in vivo techniques. Using advanced electrophysiology techniques, I will assay basket cell pinceau function in mouse models of EA1, then using multi-photon and conventional microscopy I will map local basket cell microcircuits. Finally building on in vitro experiments I will assay candidate small molecule therapies in vivo, both with electrophysiology and with behavioural test of cerebellar coordination. The project allows me to train in state-of-the-art in vitro and in vivo methods while drawing on my extensive background in neuropharmacology, biochemistry electrophysiology. This research action will also advance our understanding of paroxysmal neurological disorders and identify new therapeutic targets. |
