Ion channels determine neuronal activity and brain excitability, and their disruption is associated with ataxia, epilepsy and other neurological disorders. Mutations in the gene encoding the Kv1.1 potassium channel subunit are known to cause episodic ataxia type 1 (EA1), in which patients suffer from variable degrees of cerebellar incoordination and spontaneous muscle activity. Kv1.1 mutations exert a dominant negative effect, interfering with channel function when studied in non-neuronal cells, but their effects in neurons remain poorly understood. To determine how neuron-specific functions such as action potential generation and neurotransmitter release are affected by ion channel mutations, it is necessary to study them in neurons. Such a model could determine why different mutations in Kv1.1 result in variable phenotypes, causing a subset of patients to experience complicating features such as seizures.

The authors use lentiviruses to deliver either wild-type or mutant Kv1.1 DNA into neurons cultured on micro-islands of glial cells. Patch-clamp experiments show that the overexpression of wild-type Kv1.1 DNA decreases the excitability of neurons and interferes with neurotransmitter release. This is consistent with the known role of potassium channels in the repolarization of neurons after action potentials and in the stabilization of the resting membrane potential. A C-terminus-truncated R417stop mutant form of Kv1.1, which causes severe episodic ataxia without seizures, has the opposite effect. This mutant increases both neuronal excitability and neurotransmitter release, suggesting that a dominant negative interaction occurs between the mutant channel subunit and the endogenous potassium channels. A point mutation (T226R) that is associated with episodic ataxia complicated by contractures and epilepsy shows a different neuronal effect, with little change in excitability but increased neurotransmitter release. These findings provide insights into the mechanisms that contribute to the variable phenotypes associated with EA1.

Different mutations of the Kv1.1 potassium channel have distinct effects on neuronal function. It is possible that mutations in Kv1.1 influence its partnering with other ion channel subunits in various ways, altering the expression and location of the channels on the surface of the neuron. Understanding the effects of channel heterogeneity in the cerebellum, forebrain, spinal cord and peripheral nerve should help to understand the pathological mechanisms that lead to episodic ataxia and to identify potential areas for therapeutic intervention.

2009