Novel KCC3 mouse models to study ACCPN, a degenerative neuropathy disorder

Abstract

Among the K‐Cl cotransporters, KCC2 and KCC3 are expressed in the central nervous system where they play an important role in modulating GABA neurotransmission by lowering the intracellular neuronal Cl− concentration. Mice with KCC3 deletion are viable but exhibit a locomotor deficit due to a peripheral neuropathy called ACCPN (or Agenesis of Corpos Callosum with Peripheral Neuropathy). In order to better define the contribution of KCC3 function in the development of ACCPN, we created two novel mouse models. The first model is a knock‐in mouse harboring a single amino acid substitution (E289G), producing a full‐length but non‐functional protein. Surprisingly, this new mutant mouse was non‐viable. Genotyping of embryos and blastocysts demonstrated absence of homozygous E289G mice as early as E3.5. As both males and females were able to produce heterozygous E289G animals, these data indicate that the mutation might affect cell division and/or migration. The second mouse model allowed for tissue‐specific deletion of KCC3 through CRE recombination. To target deletion of KCC3 in specific cell types, we mated KCC3 floxed mice with a variety of transgenic CRE lines. Deletion of KCC3 in small sensory neurons, driven by the Nav1.8 Na+ channel promoter, resulted in mice that exhibited a small but significant motor coordination phenotype.