EA1-linked Kv1.1 dysfunction enhances susceptibility to cerebellar spreading depression and a transient cerebellar refractory state.

Episodic ataxia type 1 (EA1) is a neurological channelopathy caused by loss-of-function mutations in the KCNA1 gene, which encodes the Kv1.1 α-subunit of voltage-gated potassium channels. Clinically, EA1 is characterized by interictal myokymia and transient episodes of generalized ataxia. While the molecular basis of the disease is well established, the mechanisms underlying the paroxysmal nature of attacks remains unclear. Drawing parallels with migraine with aura, an episodic disorder in which cortical spreading depression (CSD), a propagating wave of neuronal and glial depolarization followed by prolonged suppression of excitability, triggers symptoms, we hypothesized that EA1 may similarly involve an increased susceptibility to cerebellar spreading depression (CeSD), driven by reduced Kv1.1 channel activity and heightened cerebellar excitability. In mouse cerebellar slices exposed to elevated extracellular K+, CeSD displayed several properties distinct from CSD, including sensitivity to AMPA and GABAA receptor antagonists, insensitivity to NMDA receptor blockade, and a markedly slower propagation rate. Notably, cerebellar slices from knock-in (KI) mice carrying the EA1-associated Kv1.1 loss-of-function mutation V408A showed significantly accelerated CeSD propagation and greater spatial spread within the molecular layer compared with wild-type counterparts. Furthermore, cerebellar slices from KI mice exhibited increased susceptibility to CeSD when challenged with elevated extracellular K+. Extracellular and patch-clamp recordings further demonstrated that CeSD induced a transient suppression of cerebellar excitatory transmission at parallel fiber-Purkinje cell synapses, with a duration resembling the temporal profile of EA1 attacks. Collectively, these findings support a central role for CeSD in the pathophysiology of EA1.