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Proposed effects of EA1-causing pathogenic variants on basket cell and Purkinje cell inhibitory outputs

The diagram shows a basket cell that has synapses on the initial segment and soma of a number of Purkinje cells from the cerebellar cortex of an unaffected individual (left) compared to an individual with EA1 (right). The reduced delayed rectifier function of EA1 heteromeric channels comprising Kv1.1 and Kv1.2 subunits, which are expressed at the presynaptic level of basket cells, may increase the membrane excitability, prolong their action potential duration, and enhance Ca²⁺ ion influx. Larger amounts of γ-aminobutyric acid (GABA) may be released from basket cell terminals reducing the inhibitory outputs of the relevant Purkinje cells. As a result, the output of the entire cerebellum to the rest of the brain may be markedly altered leading to the cerebellar symptoms characteristic of EA1 (see D'Adamo et al 1999, Figure 7).

Reused by permission of FASEB Journal