BaskAtax · Modulation of Basket cell microcircuits in cerebellar cortex paroxysmal ataxia disorders

Modulation of Basket cell microcircuits in cerebellar cortex paroxysmal ataxia disorders

Episodic neurological disorders such as migraine and epilepsy are common, yet in most cases our understanding of their origins and causes remains surprisingly basic. This in turn has hampered the development of targeted therapy for the treatment or relief of symptoms. Typically these disorders have a complex genetic pattern, nevertheless a small subgroup have a simple monogenetic origin. These rare monogenetic episodic disorders can individually affect many genes, however there is a bias towards genes linked to neurotransmission and particularly the function of the synapse the point of communication between neurons in the brain. We have studied a rare congenital neurological disorder called Episodic Ataxia Type 1 (EA1) caused by a dominant negative mutation in the Kcna1 potassium channel. Individuals with EA1 suffer from muscle twitches (myokymia) and paroxysmal events lasting from minutes to hours, characterized by loss of coordinated movement (ataxia). The cerebellum, a brain region often affected in ataxia is enriched with synaptic Kcna1 potassium channels. Consequently it is thought that EA1 mutation in Kcna1 has a pathological role in cerebellar synaptic neurotransmission. In this project it has been our objective to understand the effect of Kcna1 mutation on the function of cerebellum and to investigate potential new treatments. These experiments are not only important to individuals living with EA1, but given the crossover with other synaptic disorders has the potential to identify communalities that can be applied to the class of episodic neurological disorders as a whole. To address these objectives we have recorded the function of the cerebellum in a mouse model of EA1. Contrary to expectations we discovered that the baseline function of the cerebellum was not affected in EA1. This was supported by behavioural assay showing that motor function was retained in these mice. We interpret this to indicate that robust neuronal mechanisms function to normalize cerebellar function in EA1. However, in contrast when we challenged EA1 mice with stimulants aping a paroxysmal event differences became apparent. Using a new behavioural paradigm, we also made the unexpected discovery that male and female EA1 mice are differentially affected. Our experiments suggest that adaptation has an important role in protecting the brain in episodic neurological disorders and that how males and females respond to paroxysmal attack triggers is not necessarily the same.

Data: CORDIS, © European Union