- Awarded: 2018
- Award Type: Research
- Award #: 573779
The voltage-gated sodium (Nav), calcium (Cav) and potassium (Kv) channels that generate action potentials in neurons are among the most frequent targets of de novo mutations that cause autism. Remarkably, while the arginine residues that serve as gating charges to drive electrical excitation of these channels comprise <0.8% of their amino acid residues, they are targets of >10% of the pathogenic mutations.
By performing a survey of databases containing de novo missense mutations in autism, Larry Zweifel and Bill Catterall have identified multiple Nav, Kv and Cav channels with gating charge mutations, as well as mutations corresponding to key residues in other regions that contribute to voltage sensing. Based on a large body of previous work from Bill Catterall’s laboratory demonstrating how gating charge mutations generate a small current through the voltage sensor, termed the ‘gating pore current’ (reviewed in 1), Zweifel and Catterall hypothesize that gating charge mutations are pathogenic in autism due to continuous Na+ leak and subsequent perturbation of action potential firing.
Zweifel and Catterall propose to understand the impact of autism-associated gating charge mutations by establishing the biophysical changes in ion channels that occur upon the introduction of gating charge mutations using related bacterial channels (NavAb, KvAb and CavAb) that maintain evolutionary conservation in the voltage-sensing regions.
Using advanced techniques in viral-mediated CRISPR/Cas9 gene mutagenesis, they will also introduce these autism-associated mutations into the endogenous Nav1.2 (SCN2A) and Kv7.3 (KCNQ3) channels in mice in order to establish how these mutations impact cellular physiology in distinct cells types within the intact nervous system. In addition, they will study how these changes associated with the gating pore current impact autism-related behaviors, such as social interaction, repetitive behavior and nurturing, as well as cognitive behaviors.
Collectively, this research will help to resolve the contribution of gating pore current to neuronal dysfunction and thereby define how this large class of autism mutations alters neuronal activity patterns that contribute to autism-related phenotypes.