Key result
Autism-associated gating charge mutations in KV7 channels induced pathogenic gating pore currents that severely disrupted action potential generation and repetitive firing in mouse dopamine neurons.
Why the study?
Mutations in the voltage sensor of the voltage-gated potassium channel KV7 are frequently associated with autism spectrum disorder, but their functional consequences were unclear.
ASD-associated mutations in KV7 channels induce pathogenic gating pore currents that disrupt neuronal excitability, suggesting a novel mechanism for autism spectrum disorder.
KV7 ASD mutations may cause ionic leak; hypothesis-generating for channel-targeted therapies, requiring in vivo confirmation.
Significance Autism spectrum disorder (ASD) adversely impacts >1% of children, causing social interaction deficits, repetitive behaviors, and communication disorders. Genetic analysis of ASD has advanced dramatically through genome sequencing, which has identified >500 genes with mutations in ASD. Mutations in the voltage sensor of the voltage-gated potassium (K V ) channel K V 7 are frequently associated with ASD. We discovered that these ASD mutations cause an ionic leak through the voltage sensor, termed gating pore current. When these mutations were inserted into the genome of mouse dopamine neurons, they caused a dramatic alteration in the ability of those neurons to fire action potentials in response to electrical stimulation. These changes would impair information processing in neurons, leading to broad changes in brain function.
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El-Din et al. (2021) studied Autism spectrum disorder (preclinical models). KV7 channel gating charge mutations (e.g., R1Q, R2C, R4C) vs. Wild-type KV7 channels was evaluated on Gating pore current and action potential firing frequency. Autism-associated gating charge mutations in KV7 channels induced pathogenic gating pore currents that severely disrupted action potential generation and repetitive firing in mouse dopamine neurons.
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