Kv3 and Kv4 K+
channels have specialized gating properties that confer on neurons distinct
patterns of action potential firing. Kv3 channels activate in a depolarized
voltage range with fast activation and deactivation kinetics, and promote sustained,
high frequency firing. Kv4 channels activate at sub-threshold voltages and inactivate
from pre-open and open states via uncoupling of the voltage sensor and pore
gate. Inactivation controls the availability of Kv4-containing channels, which delay
the first spike in a train, reduce the frequency of repetitive firing, and prevent
back propagation of action potentials into dendrites. Altering the specialized gating
properties of Kv3 or Kv4 channels results in severe infant-onset diseases. Kv3.3
mutations cause spinocerebellar ataxia type 13 (SCA13), which exists in two
clinical forms that differ in the age of onset. Infant-onset SCA13 is characterized
by severe cerebellar atrophy early in life, persistent motor problems, and
intellectual disability. We found that Kv3.3 mutations that cause infant-onset
SCA13 dominantly alter activation gating with or without reducing current
amplitude. In contrast, in adult-onset SCA13, the mutant subunit reduces
current amplitude but the residual current is functionally normal. Recently, a de
novo Kv4.2 mutation, V404M, was identified by exome sequencing in identical
twins with intractable seizures in infancy and autism. This mutation
significantly impairs Kv4 inactivation in a state-dependent manner, with a more
severe effect on inactivation after opening than from pre-open closed states. Thus,
SCA13 mutations in Kv3.3 and V404M in Kv4.2 specifically alter novel gating
properties that are responsible for the specialized roles of these channels in
controlling neuronal excitability, resulting in early-onset neurological
diseases. We are using zebrafish, a lower vertebrate, to investigate the in
vivo consequences of these mutations, characterize their effects on neuronal
excitability, and identify downstream effectors that could underlie
pathogenesis in SCA13 and in epilepsy coupled with autism.